Bicyclic compounds as inhibitors of pd1/pd-l1 interaction/activation

ABSTRACT

The compounds of Formula I is described herein along with their polymorphs, stereoisomers, tautomers, prodrugs, solvates, and pharmaceutically acceptable salts thereof. The compounds described herein, their polymorphs, stereoisomers, tautomers, prodrugs, solvates, and pharmaceutically acceptable salts thereof are bicyclic compounds that are inhibitors of PD-1/PD-L1 interaction/activation.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to substituted bicyclic compounds ofFormula I along with their polymorphs, stereoisomers, tautomers,prodrugs, solvates, and pharmaceutically acceptable salts thereof whichare inhibitors of PD1/PD-L1 interaction. The present invention alsorelates to method of synthesizing the compounds of Formula I.

The compounds described herein are inhibitors of PD1/PD-L1 activationand may be used in the treatment of cancer, and other diseases orconditions associated with activation of PD1/PD-L1.

BACKGROUND OF THE INVENTION

Tumour development and survival involves the interplay between cancercells, normal stromal cells and host defence mechanisms (Vinay D. S. etal., Seminars in Cancer Biology, 2015, 35: S185-S198). Generally, CD8+cytotoxic T cells (CTLs) and CD4+ helper T (Th1) cells curb cancerdevelopment via mechanisms commonly involving the production ofinterferon (IFN)-γ and cytotoxins (Zamarron B F et al., Intl. J. Biol.Sciences, 2011, 7(5):651-658). Tumours have, however evolved a number ofmechanisms to escape immune eradications. The PD-1/PD-L1 molecularpathway is one such primary mechanism of cancer immune evasion.

PD-1 is a type 1 trans-membrane protein encoded by the PDCD1 gene. It isa member of the extended CD28/CTLA-4 immunoglobulin family and one ofthe most important inhibitory co-receptors expressed by T cells (He J.et al., Scientific Reports, 2015, 5:1-9). PD-1 is absent on resting Tcells but is induced on activated T cells. It is also expressed on Bcells, NK cells, dendritic cells (DCs) and macrophages. The programmedcell death protein (PD-1) down regulates the immune system and preventsit from killing cancerous cells present in the body. In cancer, highlevels of PD-1 are detected in tumour infiltrating T cells and thisexpression has been associated with impaired CD8+ T cell function (LeungJ et al., Immune Network, 2014, 14(6):265-276).

PD-1 has two ligands: PD-L1 (also named B7-H1; CD274) and PD-L2 (B7-DC;CD273), that are both co-inhibitory (Flies D. B. et al., Yale J. BiologyMedicine, 2011, 84(4):409-421). PD-L1, expressed on almost all murinetumour cells, is the major ligand for PD-1 mediated immune suppression.It is constitutively expressed on APCs and can be broadly induced oncells in both lymphoid tissues and non-lymphoid peripheral tissuesfollowing cellular activation (Flies D. B. et al., Yale J. BiologyMedicine, 2011, 84(4):409-421; Dong Y. et al., Oncotarget, 2017,8(2):2171-2186). The cytokine IFN-γ is particularly effective inup-regulating PD-L1 expression due to IFN-γ response elements in thePD-L1 promoter region (Lee S. J. et al., FEBS Letters, 2006,580:755-762; Flies D. B. et al., Immunotherapy, 2007, 30(3):251-260).The expression of B7-DC/PD-L2 is largely restricted to myeloid dendriticcells (DCs) and macrophages in lymphoid compartments and is not broadlyexpressed in peripheral tissues (Flies D. B. et al., Yale J. BiologyMedicine, 2011, 84(4):409-421). In cancer, PD-L1 is expressed on thesurface of tumour cells in various solid malignancies such as squamouscell carcinoma of the head and neck, melanoma, carcinomas of the brain,thyroid, thymus, esophagus, lung, breast, gastrointestinal tract,colorectum, liver, pancreas, kidney etc. (Topalian S. L. et al., Curr.Opin. Immunol., 2012, 24(2):207-212; Wang X. et al., Oncotargets andTherapy, 2016, 9:5023-5039). In hepatocellular carcinoma, melanoma andbreast cancer, PD-L1 positivity was correlated with worse prognosis(Muenst S. et al., Breast Cancer Res. Treat., 2014, 146(1):15-24; LeungJ. et al., Immune Network, 2014, 14(6):265-276; Wang Q. et al., Medicine(Baltimore), 2017, 96(18): e6369). In contrast, normal human tissuesseldom express PD-L1 protein on their cell surface, indicating thatPD-L1 can be a selective target for anti-tumour therapy (Chen L. et al.,J. Clin. Invest., 2015, 125(9):3384-3391).

Cancer microenvironment manipulates the PD-1/PD-L1 pathway; induction ofPD-L1 expression is associated with inhibition of immune responsesagainst cancer, thus permitting cancer progression and metastasis (He J.et al., Scientific Reports, 2015, 5:1-9; Bardhan K. et al., Frontiers inImmunology, 2016, 7(550):1-17). Activation of PD-1/PD-L1 pathway inducesapoptosis of activated T cells (Dong H. et al., Nature Medicine, 2002,8(8):793-800; Curiel T. J. et al., Nature Medicine, 2003, 9(5):562-567),facilitates T cell anergy and exhaustion (Barber D. L. et al., Nature,2005, 439(7077):682-687), enhances the function of regulatory T cells(Francisco L. M. et al., J. Exp. Med., 2009, 206(13):3015-3029) andinhibits the proliferation of T cells (Sheppard K. A. et al., FEBSLetters, 2004, 574:37-41; Patsoukis N. et al., Cell Cycle, 2012,11(23):4305-4309). Therefore, blocking this pathway restores theproliferation and cytotoxicity of CTLs, inhibiting the function ofregulatory T cells (Tregs), and results in decrease T cell apoptosis.

Blockade of the PD-1/PD-L1 pathway by therapeutic antibodies has beenshown to prevent inhibitory signalling from cancer cells and enablingCTLs to elicit an immune response against the target/cancer cells (ZouW. et al., Sci. Transl. Med., 2016, 8(328):328rv4; Smahel M., Int. J.Mol. Sci., 2017, 18(6):1331). A number of cancer immunotherapy agentstargeting PD-1 have been developed till date and approved for a numberof malignancies including melanoma, lung cancer, kidney cancer,Hodgkin's lymphoma, head and neck cancer and urothelial cancer. Thefirst therapeutic anti-PD-L1 antibody was approved by the FDA in May2016, for the treatment of patients with metastatic urothelial carcinomaand non-small cell lung cancer, with a number of additional therapies inthe pipeline. Currently, there are at least 500 clinical studieson-going with PD-1/PD-L1 antibodies against 20 types of solid andhaematological malignant tumours. However, there is still a need forpotent and selective small molecule inhibitors of the PD-1/PD-L1pathway.

Common drug-related adverse effects (AEs) of both anti-PD-1 andanti-PD-L antibodies include fatigue, rash, diarrhoea, pruritus,decrease appetite, arthralgia and nausea. Immune-related AEs (irAEs)such as dermatitis, colitis, hepatitis, vitiligo and thyroiditis havebeen reported and about 10% of patients develop grade 3 or 4 irAEs(Hamanishi J. et al., Int. J. Clin. Oncol., 2016, 21:462-473). The longresidence time of the monoclonal antibodies (mAbs) could contribute tothese AEs, which may be partially circumvented using a small moleculeinhibitor. In addition, studies using smaller cell penetratingbiologicals and DNA aptamers have shown to exert antibody-mimicfunctions and are advantageous over antibody for its chemicallysynthetic nature, low immunogenicity, and efficient tissue penetration(Lai W. Y. et al., Mol. Therapy—Nucl. Acids, 2016, 5: e397). Smallmolecule inhibitors, therefore, can provide increased oralbioavailability, increased bio-efficiency and shortened half-lifeactivity for a more controllable treatment, particularly in the case ofauto-immune or other adverse events.

As discussed, the PD-1/PD-L1 inhibitory compounds have vast utility inup-regulating the immune system for efficiently combating cancer.Therefore, the identification of a chemical moiety, especially smallmolecule inhibitors, that facilitates this inhibition is necessary.Therefore, the identification and development of new PD-1/PD-L1inhibitor compounds treating cancer and other diseases or conditionsassociated with activation of PD-1/PD-L1 would open new opportunities inthe realm of cancer treatment.

SUMMARY OF INVENTION

In an aspect of the present disclosure there is provided a compound ofFormula I

their polymorphs, stereoisomers, tautomers, prodrugs, solvates, andpharmaceutically acceptable salts thereof, wherein X₁ is selected from—CH₂O—, —OCH₂—, —C(O)NH— or —NHC(O)—; R₄ is selected from hydrogen,hydroxyl, C₁₋₆ alkyl, amino, —C(O)OR_(a1), C(O)NR_(b1)R_(c1), C₅₋₆ aryl,or C₁₋₆ heteroaryl, wherein C₁₋₆ alkyl is optionally substituted withone or more of the groups selected from the group consisting ofhydrogen, hydroxyl, amino, —C(O)OR_(a1), C(O)NR_(b1)R_(c1), C₅₋₆ aryl,and C₁₋₆ heteroaryl; R_(a1), R_(b1), and R_(c1) are independentlyselected from hydrogen or C₁₋₆ alkyl; X is selected from CR₃ or N; R₁,R₂, R₃, R₆, and R₇ are independently selected from hydrogen, halo, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a), SR^(a), NHOR^(a),C(O)R^(a), C(O)NR^(a)R^(a), C(O)OR^(a), OC(O)R^(a), OC(O)NR^(a)R^(a),NHR^(a), NR^(a)R^(a), NR^(a)C(O)R^(a), NR^(a)C(O)OR^(a),NR^(a)C(O)NR^(a)R^(a), C(═NR^(a))R^(a), C(═NR^(a))NR^(a)R^(a),NR^(a)C(═NR^(a))NR^(a)R^(a), NR^(a)S(O)R^(a), NR^(a)S(O)₂R^(a),NR^(a)S(O)₂NR^(a)R^(a), S(O)R^(a), S(O)NR^(a)R^(a), S(O)₂R^(a), orS(O)₂NR^(a)R^(a), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, are independently optionally substitutedwith 1, 2, 3, or 4 R^(b) substituents; R^(a) is selected from hydrogen,cyano, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, or (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10membered heterocycloalkyl)-C₁₋₄ alkyl- are independently optionallysubstituted with 1, 2, 3, 4, or 5 R^(d) substituents; R^(b) is selectedfrom halo, hydroxy, cyano, amino, nitro, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-,NHOR^(c), OR^(c), SR^(c), C(O)R^(c), C(O)NR^(c)R^(c), C(O)OR^(c),OC(O)R^(c), OC(O)NR^(c)R^(c), C(═NR^(c))NR^(c)R^(c),NR^(c)C(═NR^(c))NR^(c)R^(c), NHR^(c), NR^(c)R^(c), NR^(c)C(O)R^(c),NR^(c)C(O)OR^(c), NR^(c)C(O)NR^(c)R^(c), NR^(c)S(O)R^(c),NR^(c)S(O)₂R^(c), NR^(c)S(O)₂NR^(c)R^(c), S(O)R^(c), S(O)NR^(c)R^(c),S(O)₂R^(c) or S(O)₂NR^(c)R^(c); wherein the C₁₋₄ alkyl, C₂₋₄ alkenyl,C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-are optionally substituted with 1, 2, or 3 R^(d) substituents; R^(c) isselected from hydrogen, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, or (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10membered heterocycloalkyl)-C₁₋₄ alkyl- are optionally substituted with1, 2, 3, 4, or 5 R^(f) substituent; R^(d) is selected from cyano, amino,C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo, C₆₋₁₀ aryl, 5-10 membered heteroaryl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, NHOR^(e), OR^(e),SR^(e), C(O)R^(e), C(O)NR^(e)R^(e), C(O)OR^(e), OC(O)R^(e),OC(O)NR^(e)R^(e), NHR^(e), NR^(e)R^(e), NR^(e)C(O)R^(e),NR^(e)C(O)NR^(e)R^(e), NR^(e)C(O)OR^(e), C(═NR^(e))NR^(e)R^(e),NR^(e)C(═NR^(e))NR^(e)R^(e), NR^(e)C(═NOH)NR^(e)R^(e),NR^(e)C(═NCN)NR^(e)R^(e), S(O)R^(e), S(O)NR^(e)R^(e), S(O)₂R^(e),NR^(e)S(O)₂R^(e), NR^(e)S(O)₂NR^(e)R^(e), or S(O)₂NR^(e)R^(e), whereinthe C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are optionallysubstituted with 1, 2, or 3 R^(f) substituents; R^(f) is selected fromC₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, halogen, CN, NHOR^(g), OR^(g), SR^(g),C(O)R^(g), C(O)NR^(g)R^(g), C(O)OR^(g), OC(O)R^(g), OC(O)NR^(g)R^(g),NHR^(g), NR^(g)R^(g), NR^(g)C(O)R^(g), NR^(g)C(O)NR^(g)R^(g),NR^(g)C(O)OR^(g), C(═NR^(g))NR^(g)R^(g), NR^(g)C(═NR^(g))NR^(g)R^(g),S(O)R^(g), S(O)NR^(g)R^(g), S(O)₂R^(g), NR^(g)S(O)₂R^(g),NR^(g)S(O)₂NR^(g)R^(g), or S(O)₂NR^(g)R^(g); wherein the C₁₋₄ alkyl,C₁₋₄haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄alkyl- are optionally substituted with 1, 2, 3, 4, or 5 R^(n)substituents; R^(g) is selected from hydrogen, C₁₋₆ alkyl, C₁₋₄haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, or (4-10 membered heterocycloalkyl)-C₁₋₄alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- are optionally substituted with 1, 2, or 3R^(p) substituents; R^(n) is selected from cyano, halo, C₁₋₄ alkyl,C₃₋₁₀ cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6membered heteroaryl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄alkyl-, (5-6 membered heteroaryl)-C₁₋₄ alkyl-, (4-7 memberedheterocycloalkyl)-C₁₋₄ alkyl-, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₄ haloalkyl, R^(o), NHOR^(o), OR^(o), SR^(o), C(O)R^(o),C(O)NR^(o)R^(o), C(O)OR^(o), OC(O)R^(o), OC(O)NR^(o)R^(o), NHR^(o),NR^(o)R^(o), NR^(o)C(O)R^(o), NR^(o)C(O)NR^(o)R^(o), NR^(o)C(O)OR^(o),C(═NR)NR^(o)R^(o), NR^(o)C(═NR^(o))NR^(o)R^(o), S(O)R^(o),S(O)NR^(o)R^(o), S(O)₂R^(o), NR^(o)S(O)₂R^(o), NR^(o)S(O)₂NR^(o)R^(o),or S(O)₂NR^(o)R^(o), wherein the C₁₋₄ alkyl, C₃₋₁₀ cycloalkyl, 4-7membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-6 memberedheteroaryl)-C₁₋₄ alkyl-, (4-7 membered heterocycloalkyl)-C₁₋₄ alkyl-,C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₄haloalkyl areoptionally substituted with 1, 2 or 3 R^(q) substituents; R^(p) isselected from halo, cyano, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, NHOR^(r), OR^(r), SR^(r),C(O)R^(r), C(O)NR^(r)R^(r), C(O)OR^(r), OC(O)R^(r), OC(O)NR^(r)R^(r),NHR^(r), NR^(r)R^(r), NR^(r)C(O)R^(r), NR^(r)C(O)NR^(r)R^(r),NR^(r)C(O)OR^(r), C(═NR^(r))NR^(r)R^(r), NR^(r)C(═NR^(r))NR^(r)R^(r),NR^(r)C(═NOH)NR^(r)R^(r), NR^(r)C(═NCN)NR^(r)R^(r), S(O)R^(r),S(O)NR^(r)R^(r), S(O)₂R^(r), NR^(r)S(O)₂R^(r), NR^(r)S(O)₂NR^(r)R^(r) orS(O)₂NR^(r)R^(r), wherein the C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-are optionally substituted with 1, 2 or 3 R^(q) substituents; R^(e),R^(i), R^(k), R^(o) and R^(r) are independently selected from hydrogen,C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5 or 6-membered heteroaryl, 4-6membered heterocycloalkyl, C₁₋₄ haloalkyl, C₂₋₄ alkenyl, or C₂₋₄alkynyl, wherein the C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5 or6-membered heteroaryl, 4-6 membered heterocycloalkyl, C₂₋₄ alkenyl, andC₂₋₄ alkynyl are optionally substituted with 1, 2 or 3 R^(q)substituents; R^(q) is selected from hydroxy, cyano, amino, halo, COOH,C₁₋₆ haloalkyl, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylthio, C₅₋₆ aryl, 5-6membered heteroaryl, 4-6 membered heterocycloalkyl, C₃₋₆ cycloalkyl,NHR⁸, NR⁸R⁸, and C₁₋₄ haloalkoxy, wherein the C₁₋₆ alkyl, C₅₋₆ aryl,C₃₋₆ cycloalkyl, 4-6 membered heterocycloalkyl, and 5-6 memberedheteroaryl are optionally substituted with halo, hydroxy, cyano, COOH,amino, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₅₋₆aryl, C₃₋₁₀ cycloalkyl, 5-6 membered heteroaryl and 4-6 memberedheterocycloalkyl; R⁸ is C₁₋₆ alkyl; m is 1 or 2; Ring A is selected fromsubstituted or unsubstituted C₅₋₁₀ aryl, substituted or unsubstitutedC₃₋₆ cycloalkyl, and substituted or unsubstituted 5-10 memberedmonocyclic or bicyclic saturated or unsaturated heterocyclic ring with1-3 heteroatoms selected from N, S or O; Ring B is selected from C₅₋₁₀aryl, C₃₋₆ cycloalkyl, 5-10 membered monocyclic or bicyclic saturated orunsaturated heterocyclic ring with 1-3 heteroatoms selected from N, S orO.

In another aspect of the present disclosure there is provided a compoundof Formula II

their polymorphs, stereoisomers, tautomers, prodrugs, solvates, andpharmaceutically acceptable salts thereof,wherein X₁ is selected from —CH₂O—, —OCH₂—, —C(O)NH— or —NHC(O)—;R₄ is selected from hydrogen, hydroxyl, C₁₋₆ alkyl, amino, —C(O)OR_(a1),C(O)NR_(b1)R_(c1), C₅₋₆ aryl, or C₁₋₆ heteroaryl, wherein C₁₋₆ alkyl isoptionally substituted with one or more of the groups selected from thegroup consisting of hydrogen, hydroxyl, amino, —C(O)OR_(a1),C(O)NR_(b1)R_(c1), C₅₋₆ aryl, and C₁₋₆ heteroaryl;R_(a1), R_(b1), and R_(c1) are independently selected from hydrogen orC₁₋₆ alkyl;R₅ is selected from C₁₋₄ alkyl, cyano, or C₁₋₄ haloalkyl;R₁, R₂, R₃, R₆, and R₇ are independently selected from hydrogen, halo,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a), SR^(a), NHOR^(a),C(O)R^(a), C(O)NR^(a)R^(a), C(O)OR^(a), OC(O)R^(a), OC(O)NR^(a)R^(a),NHR^(a), NR^(a)R^(a), NR^(a)C(O)R^(a), NR^(a)C(O)OR^(a),NR^(a)C(O)NR^(a)R^(a), C(═NR^(a))R^(a), C(═NR^(a))NR^(a)R^(a),NR^(a)C(═NR^(a))NR^(a)R^(a), NR^(a)S(O)R^(a), NR^(a)S(O)₂R^(a),NR^(a)S(O)₂NR^(a)R^(a), S(O)R^(a), S(O)NR^(a)R^(a), S(O)₂R^(a), orS(O)₂NR^(a)R^(a), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, are independently optionally substitutedwith 1, 2, 3, or 4 R^(b) substituents; R^(a) is selected from hydrogen,cyano, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, or (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10membered heterocycloalkyl)-C₁₋₄ alkyl- are independently optionallysubstituted with 1, 2, 3, 4, or 5 R^(d) substituents;R^(b) is selected from halo, hydroxy, cyano, amino, nitro, C₁₋₄ alkyl,C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, NHOR^(c), OR^(c), SR^(c), C(O)R^(c),C(O)NR^(c)R^(c), C(O)OR^(c), OC(O)R^(c), OC(O)NR^(c)R^(c),C(═NR^(c))NR^(c)R^(c), NR^(c)C(═NR^(c))NR^(c)R^(c), NHR^(c),NR^(c)R^(c), NR^(c)C(O)R^(c), NR^(c)C(O)OR^(c), NR^(c)C(O)NR^(c)R^(c),NR^(c)S(O)R^(c), NR^(c)S(O)₂R^(c), NR^(c)S(O)₂NR^(c)R^(c), S(O)R^(c),S(O)NR^(c)R^(c), S(O)₂R^(c) or S(O)₂NR^(c)R^(c); wherein the C₁₋₄ alkyl,C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- are optionally substituted with 1, 2, or 3R^(d) substituents;R^(d) is selected from cyano, amino, C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo,C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, NHOR^(e), OR^(e), SR^(e), C(O)R^(e),C(O)NR^(e)R^(e), C(O)OR^(e), OC(O)R^(e), OC(O)NR^(e)R^(e), NHR^(e),NR^(e)R^(e), NR^(e)C(O)R^(e), NR^(e)C(O)NR^(e)R^(e), NR^(e)C(O)OR^(e),C(═NR^(e))NR^(e)R^(e), NR^(e)C(═NR^(e))NR^(e)R^(e),NR^(e)C(═NOH)NR^(e)R^(e), NR^(e)C(═NCN)NR^(e)R^(e), S(O)R^(e),S(O)NR^(e)R^(e), S(O)₂R^(e), NR^(e)S(O)₂R^(e), NR^(e)S(O)₂NR^(e)R^(e),or S(O)₂NR^(e)R^(e), wherein the C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- are optionally substituted with 1, 2, or 3R^(f) substituents;R^(c) is selected from hydrogen, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, or(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are optionally substitutedwith 1, 2, 3, 4, or 5 R^(f) substituent;R^(f) is selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, halogen, CN, NHOR^(g), OR^(g), SR^(g),C(O)R^(g), C(O)NR^(g)R^(g), C(O)OR^(g), OC(O)R^(g), OC(O)NR^(g)R^(g),NHR^(g), NR^(g)R^(g), NR^(g)C(O)R^(g), NR^(g)C(O)NR^(g)R^(g),NR^(g)C(O)OR^(g), C(═NR^(g))NR^(g)R^(g), NR^(g)C(═NR^(g))NR^(g)R^(g),S(O)R^(g), S(O)NR^(g)R^(g), S(O)₂R^(g), NR^(g)S(O)₂R^(g),NR^(g)S(O)₂NR^(g)R^(g), or S(O)₂NR^(g)R^(g); wherein the C₁₋₄ alkyl,C₁₋₄haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄alkyl- are optionally substituted with 1, 2, 3, 4, or 5 R^(n)substituents; R^(n) is selected from cyano, halo, C₁₋₄ alkyl, C₃₋₁₀cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 memberedheteroaryl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-6membered heteroaryl)-C₁₋₄ alkyl-, (4-7 membered heterocycloalkyl)-C₁₋₄alkyl-, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl,R^(o), NHOR^(o), OR^(o), SR^(o), C(O)R^(o), C(O)NR^(o)R^(o), C(O)OR^(o),OC(O)R^(o), OC(O)NR^(o)R^(o), NHR^(o), NR^(o)R^(o), NR^(o)C(O)R^(o),NR^(o)C(O)NR^(o)R^(o), NR^(o)C(O)OR^(o), C(═NR)NR^(o)R^(o),NR^(o)C(═NR^(o))NR^(o)R^(o), S(O)R^(o), S(O)NR^(o)R^(o), S(O)₂R^(o),NR^(o)S(O)₂R^(o), NR^(o)S(O)₂NR^(o)R^(o), or S(O)₂NR^(o)R^(o), whereinthe C₁₋₄ alkyl, C₃₋₁₀ cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀aryl, 5-6 membered heteroaryl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-6 membered heteroaryl)-C₁₋₄ alkyl-, (4-7membered heterocycloalkyl)-C₁₋₄ alkyl-, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl,C₂₋₆ alkynyl and C₁₋₄haloalkyl are optionally substituted with 1, 2 or 3R^(q) substituents;R^(g) is selected from hydrogen, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃_10 cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, or(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are optionally substitutedwith 1, 2, or 3 R^(p) substituents;R^(p) is selected from halo, cyano, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-,NHOR^(r), OR^(r), SR^(r), C(O)R^(r), C(O)NR^(r)R^(r), C(O)OR^(r),OC(O)R^(r), OC(O)NR^(r)R^(r), NHR^(r), NR^(r)R^(r), NR^(r)C(O)R^(r),NR^(r)C(O)NR^(r)R^(r), NR^(r)C(O)OR^(r), C(═NR^(r))NR^(r)R^(r),NR^(r)C(═NR^(r))NR^(r)R^(r), NR^(r)C(═NOH)NR^(r)R^(r),NR^(r)C(═NCN)NR^(r)R^(r), S(O)R^(r), S(O)NR^(r)R^(r), S(O)₂R^(r),NR^(r)S(O)₂R^(r), NR^(r)S(O)₂NR^(r)R^(r) or S(O)₂NR^(r)R^(r), whereinthe C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- are optionally substituted with 1, 2 or 3R^(q) substituents;R^(e), R^(i), R^(k), R^(o) and R^(r) are independently selected fromhydrogen, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5 or 6-memberedheteroaryl, 4-6 membered heterocycloalkyl, C₁₋₄ haloalkyl, C₂₋₄ alkenyl,or C₂₋₄ alkynyl, wherein the C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5or 6-membered heteroaryl, 4-6 membered heterocycloalkyl, C₂₋₄ alkenyl,and C₂₋₄ alkynyl are optionally substituted with 1, 2 or 3 R^(q)substituents;R^(q) is selected from hydroxy, cyano, amino, halo, COOH, C₁₋₆haloalkyl, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylthio, C₅₋₆ aryl, 5-6membered heteroaryl, 4-6 membered heterocycloalkyl, C₃₋₆ cycloalkyl,NHR⁸, NR⁸R⁸, and C₁₋₄ haloalkoxy, wherein the C₁₋₆ alkyl, C₅₋₆ aryl,C₃₋₆ cycloalkyl, 4-6 membered heterocycloalkyl, and 5-6 memberedheteroaryl are optionally substituted with halo, hydroxy, cyano, COOH,amino, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₅₋₆aryl, C₃₋₁₀ cycloalkyl, 5-6 membered heteroaryl and 4-6 memberedheterocycloalkyl;R⁸ is C₁₋₆ alkyl;Ring B is selected from C₅₋₁₀ aryl, C₃₋₆ cycloalkyl, 5-10 memberedmonocyclic or bicyclic saturated or unsaturated heterocyclic ring with1-3 heteroatoms selected from N, S or O.

In yet another aspect of the present disclosure there is provided acompound of Formula III

their polymorphs, stereoisomers, tautomers, prodrugs, solvates, andpharmaceutically acceptable salts thereof,wherein X₁ is selected from —CH₂O—, —OCH₂—, —C(O)NH— or —NHC(O)—;R₄ is selected from hydrogen, hydroxyl, C₁₋₆ alkyl, amino, —C(O)OR_(a1),C(O)NR_(b1)R_(c1), C₅₋₆ aryl, or C₁₋₆ heteroaryl; wherein C₁₋₆ alkyl isoptionally substituted with one or more of the groups selected from thegroup consisting of hydrogen, hydroxyl, amino, —C(O)OR_(a1),C(O)NR_(b1)R_(c1), C₅₋₆ aryl, and C₁₋₆ heteroaryl;R_(a1), R_(b1), and R_(c1) are independently selected from hydrogen orC₁₋₆ alkyl;R₅ is selected from C₁₋₄ alkyl, cyano, or C₁₋₄ haloalkyl;R₁, R₂, R₃, R₆, and R₇ are independently selected from hydrogen, halo,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a), SR^(a), NHOR^(a),C(O)R^(a), C(O)NR^(a)R^(a), C(O)OR^(a), OC(O)R^(a), OC(O)NR^(a)R^(a),NHR^(a), NR^(a)R^(a), NR^(a)C(O)R^(a), NR^(a)C(O)OR^(a),NR^(a)C(O)NR^(a)R^(a), C(═NR^(a))R^(a), C(═NR^(a))NR^(a)R^(a),NR^(a)C(═NR^(a))NR^(a)R^(a), NR^(a)S(O)R^(a), NR^(a)S(O)₂R^(a),NR^(a)S(O)₂NR^(a)R^(a), S(O)R^(a), S(O)NR^(a)R^(a), S(O)₂R^(a), orS(O)₂NR^(a)R^(a), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, are independently optionally substitutedwith 1, 2, 3, or 4 R^(b) substituents;R^(a) is selected from hydrogen, cyano, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, or(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are independentlyoptionally substituted with 1, 2, 3, 4, or 5 R^(d) substituents;R^(b) is selected from halo, hydroxy, cyano, amino, nitro, C₁₋₄ alkyl,C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, NHOR^(c), OR^(c), SR^(c), C(O)R^(c),C(O)NR^(c)R^(c), C(O)OR^(c), OC(O)R^(c), OC(O)NR^(c)R^(c),C(═NR^(c))NR^(c)R^(c), NR^(c)C(═NR^(c))NR^(c)R^(c), NHR^(c),NR^(c)R^(c), NR^(c)C(O)R^(c), NR^(c)C(O)OR^(c), NR^(c)C(O)NR^(c)R^(c),NR^(c)S(O)R^(c), NR^(c)S(O)₂R^(c), NR^(c)S(O)₂NR^(c)R^(c), S(O)R^(c),S(O)NR^(c)R^(c), S(O)₂R^(c) or S(O)₂NR^(c)R^(c); wherein the C₁₋₄ alkyl,C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- are optionally substituted with 1, 2, or 3R^(d) substituents;R^(d) is selected from cyano, amino, C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo,C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, NHOR^(e), OR^(e), SR^(e), C(O)R^(e),C(O)NR^(e)R^(e), C(O)OR^(e), OC(O)R^(e), OC(O)NR^(e)R^(e), NHR^(e),NR^(e)R^(e), NR^(e)C(O)R^(e), NR^(e)C(O)NR^(e)R^(e), NR^(e)C(O)OR^(e),C(═NR^(e))NR^(e)R^(e), NR^(e)C(═NR^(e))NR^(e)R^(e),NR^(e)C(═NOH)NR^(e)R^(e), NR^(e)C(═NCN)NR^(e)R^(e), S(O)R^(e),S(O)NR^(e)R^(e), S(O)₂R^(e), NR^(e)S(O)₂R^(e), NR^(e)S(O)₂NR^(e)R^(e),or S(O)₂NR^(e)R^(e), wherein the C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- are optionally substituted with 1, 2, or 3R^(f) substituents;R^(f) is selected from hydrogen, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, or(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are optionally substitutedwith 1, 2, 3, 4, or 5 R^(f) substituent;R^(f) is selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, halogen, CN, NHOR^(g), OR^(g), SR^(g),C(O)R^(g), C(O)NR^(g)R^(g), C(O)OR^(g), OC(O)R^(g), OC(O)NR^(g)R^(g),NHR^(g), NR^(g)R^(g), NR^(g)C(O)R^(g), NR^(g)C(O)NR^(g)R^(g),NR^(g)C(O)OR^(g), C(═NR^(g))NR^(g)R^(g), NR^(g)C(═NR^(g))NR^(g)R^(g),S(O)R^(g), S(O)NR^(g)R^(g), S(O)₂R^(g), NR^(g)S(O)₂R^(g),NR^(g)S(O)₂NR^(g)R^(g), or S(O)₂NR^(g)R^(g); wherein the C₁₋₄ alkyl,C₁₋₄haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄alkyl- are optionally substituted with 1, 2, 3, 4, or 5 R^(n)substituents;R^(n) is selected from cyano, halo, C₁_₄ alkyl, C₃₋₁₀ cycloalkyl, 4-7membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-6 memberedheteroaryl)-C₁₋₄ alkyl-, (4-7 membered heterocycloalkyl)-C₁₋₄ alkyl-,C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl, R^(o),NHOR^(o), OR^(o), SR^(o), C(O)R^(o), C(O)NR^(o)R^(o), C(O)OR^(o),OC(O)R^(o), OC(O)NR^(o)R^(o), NHR^(o), NR^(o)R^(o), NR^(o)C(O)R^(o),NR^(o)C(O)NR^(o)R^(o), NR^(o)C(O)OR^(o), C(═NR)NR^(o)R^(o),NR^(o)C(═NR^(o))NR^(o)R^(o), S(O)R^(o), S(O)NR^(o)R^(o), S(O)₂R^(o),NR^(o)S(O)₂R^(o), NR^(o)S(O)₂NR^(o)R^(o), or S(O)₂NR^(o)R^(o), whereinthe C₁₋₄ alkyl, C₃₋₁₀ cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀aryl, 5-6 membered heteroaryl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-6 membered heteroaryl)-C₁₋₄ alkyl-, (4-7membered heterocycloalkyl)-C₁₋₄ alkyl-, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl,C₂₋₆ alkynyl and C₁₋₄haloalkyl are optionally substituted with 1, 2 or 3R^(q) substituents;R^(g) is selected from hydrogen, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, or(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are optionally substitutedwith 1, 2, or 3 R^(p) substituents;R^(p) is selected from halo, cyano, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-,NHOR^(r), OR^(r), SR^(r), C(O)R^(r), C(O)NR^(r)R^(r), C(O)OR^(r),OC(O)R^(r), OC(O)NR^(r)R^(r), NHR^(r), NR^(r)R^(r), NR^(r)C(O)R^(r),NR^(r)C(O)NR^(r)R^(r), NR^(r)C(O)OR^(r), C(═NR^(r))NR^(r)R^(r),NR^(r)C(═NR^(r))NR^(r)R^(r), NR^(r)C(═NOH)NR^(r)R^(r),NR^(r)C(═NCN)NR^(r)R^(r), S(O)R^(r), S(O)NR^(r)R^(r), S(O)₂R^(r),NR^(r)S(O)₂R^(r), NR^(r)S(O)₂NR^(r)R^(r) or S(O)₂NR^(r)R^(r), whereinthe C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- are optionally substituted with 1, 2 or 3R^(q) substituents;R^(e), R^(i), R^(k), R^(o) and R^(r) are independently selected fromhydrogen, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5 or 6-memberedheteroaryl, 4-6 membered heterocycloalkyl, C₁₋₄ haloalkyl, C₂₋₄ alkenyl,or C₂₋₄ alkynyl, wherein the C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5or 6-membered heteroaryl, 4-6 membered heterocycloalkyl, C₂₋₄ alkenyl,and C₂₋₄ alkynyl are optionally substituted with 1, 2 or 3 R^(q)substituents;R^(q) is selected from hydroxy, cyano, amino, halo, COOH, C₁₋₆haloalkyl, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylthio, C₅₋₆ aryl, 5-6membered heteroaryl, 4-6 membered heterocycloalkyl, C₃₋₆ cycloalkyl,NHR⁸, NR⁸R⁸, and C₁₋₄ haloalkoxy, wherein the C₁₋₆ alkyl, C₅₋₆ aryl,C₃₋₆ cycloalkyl, 4-6 membered heterocycloalkyl, and 5-6 memberedheteroaryl are optionally substituted with halo, hydroxy, cyano, COOH,amino, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₅₋₆aryl, C₃₋₁₀ cycloalkyl, 5-6 membered heteroaryl and 4-6 memberedheterocycloalkyl;R⁸ is C₁₋₆ alkyl.

In an aspect of the present disclosure there is provided a compound ofFormula IV

their polymorphs, stereoisomers, tautomers, prodrugs, solvates, andpharmaceutically acceptable salts thereof,wherein R₅ is selected from C₁₋₄ alkyl, cyano, or C₁₋₄ haloalkyl;R₁, R₂, R₃, R₆, and R₇ are independently selected from hydrogen, halo,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a), SR^(a), NHOR^(a),C(O)R^(a), C(O)NR^(a)R^(a), C(O)OR^(a), OC(O)R^(a), OC(O)NR^(a)R^(a),NHR^(a), NR^(a)R^(a), NR^(a)C(O)R^(a), NR^(a)C(O)OR^(a),NR^(a)C(O)NR^(a)R^(a), C(═NR^(a))R^(a), C(═NR^(a))NR^(a)R^(a),NR^(a)C(═NR^(a))NR^(a)R^(a), NR^(a)S(O)R^(a), NR^(a)S(O)₂R^(a),NR^(a)S(O)₂NR^(a)R^(a), S(O)R^(a), S(O)NR^(a)R^(a), S(O)₂R^(a), orS(O)₂NR^(a)R^(a), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, are independently optionally substitutedwith 1, 2, 3, or 4 R^(b) substituents;R^(a) is selected from hydrogen, cyano, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, or(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are independentlyoptionally substituted with 1, 2, 3, 4, or 5 R^(d) substituents;R^(b) is selected from halo, hydroxy, cyano, amino, nitro, C₁₋₄ alkyl,C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, NHOR^(c), OR^(c), SR^(c), C(O)R^(c),C(O)NR^(c)R^(c), C(O)OR^(c), OC(O)R^(c), OC(O)NR^(c)R^(c),C(═NR^(c))NR^(c)R^(c), NR^(c)C(═NR^(c))NR^(c)R^(c), NHR^(c),NR^(c)R^(c), NR^(c)C(O)R^(c), NR^(c)C(O)OR^(c), NR^(c)C(O)NR^(c)R^(c),NR^(c)S(O)R^(c), NR^(c)S(O)₂R^(c), NR^(c)S(O)₂NR^(c)R^(c), S(O)R^(c),S(O)NR^(c)R^(c), S(O)₂R^(c) or S(O)₂NR^(c)R^(c); wherein the C₁₋₄ alkyl,C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- are optionally substituted with 1, 2, or 3R^(d) substituents;R^(d) is selected from cyano, amino, C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo,C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, NHOR^(e), OR^(e), SR^(e), C(O)R^(e),C(O)NR^(e)R^(e), C(O)OR^(e), OC(O)R^(e), OC(O)NR^(e)R^(e), NHR^(e),NR^(e)R^(e), NR^(e)C(O)R^(e), NR^(e)C(O)NR^(e)R^(e), NR^(e)C(O)OR^(e),C(═NR^(e))NR^(e)R^(e), NR^(e)C(═NR^(e))NR^(e)R^(e),NR^(e)C(═NOH)NR^(e)R^(e), NR^(e)C(═NCN)NR^(e)R^(e), S(O)R^(e),S(O)NR^(e)R^(e), S(O)₂R^(e), NR^(e)S(O)₂R^(e), NR^(e)S(O)₂NR^(e)R^(e),or S(O)₂NR^(e)R^(e), wherein the C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- are optionally substituted with 1, 2, or 3R^(f) substituents;R^(f) is selected from hydrogen, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, or(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are optionally substitutedwith 1, 2, 3, 4, or 5 R^(f) substituent;R^(f) is selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, halogen, CN, NHOR^(g), OR^(g), SR^(g),C(O)R^(g), C(O)NR^(g)R^(g), C(O)OR^(g), OC(O)R^(g), OC(O)NR^(g)R^(g),NHR^(g), NR^(g)R^(g), NR^(g)C(O)R^(g), NR^(g)C(O)NR^(g)R^(g),NR^(g)C(O)OR^(g), C(═NR^(g))NR^(g)R^(g), NR^(g)C(═NR^(g))NR^(g)R^(g),S(O)R^(g), S(O)NR^(g)R^(g), S(O)₂R^(g), NR^(g)S(O)₂R^(g),NR^(g)S(O)₂NR^(g)R^(g), or S(O)₂NR^(g)R^(g); wherein the C₁₋₄ alkyl,C₁₋₄haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄alkyl- are optionally substituted with 1, 2, 3, 4, or 5 R^(n)substituents;R^(n) is selected from cyano, halo, C₁₋₄ alkyl, C₃₋₁₀ cycloalkyl, 4-7membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-6 memberedheteroaryl)-C₁₋₄ alkyl-, (4-7 membered heterocycloalkyl)-C₁₋₄ alkyl-,C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl, R^(o),NHOR^(o), OR^(o), SR^(o), C(O)R^(o), C(O)NR^(o)R^(o), C(O)OR^(o),OC(O)R^(o), OC(O)NR^(o)R^(o), NHR^(o), NR^(o)R^(o), NR^(o)C(O)R^(o),NR^(o)C(O)NR^(o)R^(o), NR^(o)C(O)OR^(o), C(═NR)NR^(o)R^(o),NR^(o)C(═NR^(o))NR^(o)R^(o), S(O)R^(o), S(O)NR^(o)R^(o), S(O)₂R^(o),NR^(o)S(O)₂R^(o), NR^(o)S(O)₂NR^(o)R^(o), or S(O)₂NR^(o)R^(o), whereinthe C₁₋₄ alkyl, C₃₋₁₀ cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀aryl, 5-6 membered heteroaryl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-6 membered heteroaryl)-C₁₋₄ alkyl-, (4-7membered heterocycloalkyl)-C₁₋₄ alkyl-, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl,C₂₋₆ alkynyl and C₁₋₄haloalkyl are optionally substituted with 1, 2 or 3R^(q) substituents;R^(g) is selected from hydrogen, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, or(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are optionally substitutedwith 1, 2, or 3 R^(p) substituents;R^(p) is selected from halo, cyano, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-,NHOR^(r), OR^(r), SR^(r), C(O)R^(r), C(O)NR^(r)R^(r), C(O)OR^(r),OC(O)R^(r), OC(O)NR^(r)R^(r), NHR^(r), NR^(r)R^(r), NR^(r)C(O)R^(r),NR^(r)C(O)NR^(r)R^(r), NR^(r)C(O)OR^(r), C(═NR^(r))NR^(r)R^(r),NR^(r)C(═NR^(r))NR^(r)R^(r), NR^(r)C(═NOH)NR^(r)R^(r),NR^(r)C(═NCN)NR^(r)R^(r), S(O)R^(r), S(O)NR^(r)R^(r), S(O)₂R^(r),NR^(r)S(O)₂R^(r), NR^(r)S(O)₂NR^(r)R^(r) or S(O)₂NR^(r)R^(r), whereinthe C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- are optionally substituted with 1, 2 or 3R^(q) substituents;R^(e), R^(i), R^(k), R^(o) and R^(r) are independently selected fromhydrogen, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5 or 6-memberedheteroaryl, 4-6 membered heterocycloalkyl, C₁₋₄ haloalkyl, C₂₋₄ alkenyl,or C₂₋₄ alkynyl, wherein the C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5or 6-membered heteroaryl, 4-6 membered heterocycloalkyl, C₂₋₄ alkenyl,and C₂₋₄ alkynyl are optionally substituted with 1, 2 or 3 R^(q)substituents;R^(q) is selected from hydroxy, cyano, amino, halo, COOH, C₁₋₆haloalkyl, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylthio, C₅₋₆ aryl, 5-6membered heteroaryl, 4-6 membered heterocycloalkyl, C₃₋₆ cycloalkyl,NHR⁸, NR⁸R⁸, and C₁₋₄ haloalkoxy, wherein the C₁₋₆ alkyl, C₅₋₆ aryl,C₃₋₆ cycloalkyl, 4-6 membered heterocycloalkyl, and 5-6 memberedheteroaryl are optionally substituted with halo, hydroxy, cyano, COOH,amino, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₅₋₆aryl, C₃₋₁₀ cycloalkyl, 5-6 membered heteroaryl and 4-6 memberedheterocycloalkyl;R⁸ is C₁₋₆ alkyl.

In an aspect of the present disclosure there is provided a compound ofFormula V

their polymorphs, stereoisomers, tautomers, prodrugs, solvates, andpharmaceutically acceptable salts thereof,wherein R₅ is selected from C₁₋₄ alkyl, cyano, or C₁₋₄ haloalkyl;R₄ is selected from hydrogen, hydroxyl, C₁₋₆ alkyl, amino, —C(O)OR_(a1),C(O)NR_(b1)R_(c1), C₅₋₆ aryl, or C₁₋₆ heteroaryl; wherein C₁₋₆ alkyl isoptionally substituted with one or more of the groups selected from thegroup consisting of hydrogen, hydroxyl, amino, —C(O)OR_(a1),C(O)NR_(b1)R_(c1), C₅₋₆ aryl, and C₁₋₆ heteroaryl;R_(a1), R_(b1), and R_(c1) are independently selected from hydrogen orC₁₋₆ alkyl;R₁, R₂, R₃, R₆, and R₇ are independently selected from hydrogen, halo,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a), SR^(a), NHOR^(a),C(O)R^(a), C(O)NR^(a)R^(a), C(O)OR^(a), OC(O)R^(a), OC(O)NR^(a)R^(a),NHR^(a), NR^(a)R^(a), NR^(a)C(O)R^(a), NR^(a)C(O)OR^(a),NR^(a)C(O)NR^(a)R^(a), C(═NR^(a))R^(a), C(═NR^(a))NR^(a)R^(a),NR^(a)C(═NR^(a))NR^(a)R^(a), NR^(a)S(O)R^(a), NR^(a)S(O)₂R^(a),NR^(a)S(O)₂NR^(a)R^(a), S(O)R^(a), S(O)NR^(a)R^(a), S(O)₂R^(a), orS(O)₂NR^(a)R^(a), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, are independently optionally substitutedwith 1, 2, 3, or 4 R^(b) substituents;R^(a) is selected from hydrogen, cyano, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, or(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are independentlyoptionally substituted with 1, 2, 3, 4, or 5 R^(d) substituents;R^(b) is selected from halo, hydroxy, cyano, amino, nitro, C₁₋₄ alkyl,C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, NHOR^(c), OR^(c), SR^(c), C(O)R^(c),C(O)NR^(c)R^(c), C(O)OR^(c), OC(O)R^(c), OC(O)NR^(c)R^(c),C(═NR^(c))NR^(c)R^(c), NR^(c)C(═NR^(c))NR^(c)R^(c), NHR^(c),NR^(c)R^(c), NR^(c)C(O)R^(c), NR^(c)C(O)OR^(c), NR^(c)C(O)NR^(c)R^(c),NR^(c)S(O)R^(c), NR^(c)S(O)₂R^(c), NR^(c)S(O)₂NR^(c)R^(c), S(O)R^(c),S(O)NR^(c)R^(c), S(O)₂R^(c) or S(O)₂NR^(c)R^(c); wherein the C₁₋₄ alkyl,C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- are optionally substituted with 1, 2, or 3R^(d) substituents;R^(d) is selected from cyano, amino, C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo,C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, NHOR^(e), OR^(e), SR^(e), C(O)R^(e),C(O)NR^(e)R^(e), C(O)OR^(e), OC(O)R^(e), OC(O)NR^(e)R^(e), NHR^(e),NR^(e)R^(e), NR^(e)C(O)R^(e), NR^(e)C(O)NR^(e)R^(e), NR^(e)C(O)OR^(e),C(═NR^(e))NR^(e)R^(e), NR^(e)C(═NR^(e))NR^(e)R^(e),NR^(e)C(═NOH)NR^(e)R^(e), NR^(e)C(═NCN)NR^(e)R^(e), S(O)R^(e),S(O)NR^(e)R^(e), S(O)₂R^(e), NR^(e)S(O)₂R^(e), NR^(e)S(O)₂NR^(e)R^(e),or S(O)₂NR^(e)R^(e), wherein the C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- are optionally substituted with 1, 2, or 3R^(f) substituents;R^(f) is selected from hydrogen, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, or(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are optionally substitutedwith 1, 2, 3, 4, or 5 R^(f) substituent;R^(f) is selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, halogen, CN, NHOR^(g), OR^(g), SR^(g),C(O)R^(g), C(O)NR^(g)R^(g), C(O)OR^(g), OC(O)R^(g), OC(O)NR^(g)R^(g),NHR^(g), NR^(g)R^(g), NR^(g)C(O)R^(g), NR^(g)C(O)NR^(g)R^(g),NR^(g)C(O)OR^(g), C(═NR^(g))NR^(g)R^(g), NR^(g)C(═NR^(g))NR^(g)R^(g),S(O)R^(g), S(O)NR^(g)R^(g), S(O)₂R^(g), NR^(g)S(O)₂R^(g),NR^(g)S(O)₂NR^(g)R^(g), or S(O)₂NR^(g)R^(g); wherein the C₁₋₄ alkyl,C₁₋₄haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄alkyl- are optionally substituted with 1, 2, 3, 4, or 5 R^(n)substituents;R^(n) is selected from cyano, halo, C₁₋₄ alkyl, C₃₋₁₀ cycloalkyl, 4-7membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-6 memberedheteroaryl)-C₁₋₄ alkyl-, (4-7 membered heterocycloalkyl)-C₁₋₄ alkyl-,C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl, R^(o),NHOR^(o), OR^(o), SR^(o), C(O)R^(o), C(O)NR^(o)R^(o), C(O)OR^(o),OC(O)R^(o), OC(O)NR^(o)R^(o), NHR^(o), NR^(o)R^(o), NR^(o)C(O)R^(o),NR^(o)C(O)NR^(o)R^(o), NR^(o)C(O)OR^(o), C(═NR)NR^(o)R^(o),NR^(o)C(═NR^(o))NR^(o)R^(o), S(O)R^(o), S(O)NR^(o)R^(o), S(O)₂R^(o),NR^(o)S(O)₂R^(o), NR^(o)S(O)₂NR^(o)R^(o), or S(O)₂NR^(o)R^(o), whereinthe C₁₋₄ alkyl, C₃₋₁₀ cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀aryl, 5-6 membered heteroaryl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-6 membered heteroaryl)-C₁₋₄ alkyl-, (4-7membered heterocycloalkyl)-C₁₋₄ alkyl-, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl,C₂₋₆ alkynyl and C₁₋₄haloalkyl are optionally substituted with 1, 2 or 3R^(q) substituents;R^(g) is selected from hydrogen, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, or(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are optionally substitutedwith 1, 2, or 3 R^(p) substituents;R^(p) is selected from halo, cyano, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-,NHOR^(r), OR^(r), SR^(r), C(O)R^(r), C(O)NR^(r)R^(r), C(O)OR^(r),OC(O)R^(r), OC(O)NR^(r)R^(r), NHR^(r), NR^(r)R^(r), NR^(r)C(O)R^(r),NR^(r)C(O)NR^(r)R^(r), NR^(r)C(O)OR^(r), C(═NR)NR^(r)R^(r),NR^(r)C(═NR^(r))NR^(r)R^(r), NR^(r)C(═NOH)NR^(r)R^(r),NR^(r)C(═NCN)NR^(r)R^(r), S(O)R^(r), S(O)NR^(r)R^(r), S(O)₂R^(r),NR^(r)S(O)₂R^(r), NR^(r)S(O)₂NR^(r)R^(r) or S(O)₂NR^(r)R^(r), whereinthe C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- are optionally substituted with 1, 2 or 3R^(q) substituents;R^(e), R^(i), R^(k), R^(o) and R^(r) are independently selected fromhydrogen, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5 or 6-memberedheteroaryl, 4-6 membered heterocycloalkyl, C₁₋₄ haloalkyl, C₂₋₄ alkenyl,or C₂₋₄ alkynyl, wherein the C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5or 6-membered heteroaryl, 4-6 membered heterocycloalkyl, C₂₋₄ alkenyl,and C₂₋₄ alkynyl are optionally substituted with 1, 2 or 3 R^(q)substituents;R^(q) is selected from hydroxy, cyano, amino, halo, COOH, C₁₋₆haloalkyl, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylthio, C₅₋₆ aryl, 5-6membered heteroaryl, 4-6 membered heterocycloalkyl, C₃₋₆ cycloalkyl,NHR⁸, NR⁸R⁸, and C₁₋₄ haloalkoxy, wherein the C₁₋₆ alkyl, C₅₋₆ aryl,C₃₋₆ cycloalkyl, 4-6 membered heterocycloalkyl, and 5-6 memberedheteroaryl are optionally substituted with halo, hydroxy, cyano, COOH,amino, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₅₋₆aryl, C₃₋₁₀ cycloalkyl, 5-6 membered heteroaryl and 4-6 memberedheterocycloalkyl;R⁸ is C₁₋₆ alkyl.

In an aspect of the present disclosure there is provided a compound ofFormula VI

their polymorphs, stereoisomers, tautomers, prodrugs, solvates, andpharmaceutically acceptable salts thereof,wherein R₅ is selected from C₁₋₄ alkyl, cyano, or C₁₋₄ haloalkyl;R₄ is selected from hydrogen, hydroxyl, C₁₋₆ alkyl, amino, —C(O)OR_(a1),C(O)NR_(b1)R_(c1), C₅₋₆ aryl, or C₁₋₆ heteroaryl; wherein C₁₋₆ alkyl isoptionally substituted with one or more of the groups selected from thegroup consisting of hydrogen, hydroxyl, amino, —C(O)OR_(a1),C(O)NR_(b1)R_(c1), C₅₋₆ aryl, and C₁₋₆ heteroaryl;R_(a1), R_(b1), and R_(c1) are independently selected from hydrogen orC₁₋₆ alkyl;R₁, R₂, R₃, R₆, and R₇ are independently selected from hydrogen, halo,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a), SR^(a), NHOR^(a),C(O)R^(a), C(O)NR^(a)R^(a), C(O)OR^(a), OC(O)R^(a), OC(O)NR^(a)R^(a),NHR^(a), NR^(a)R^(a), NR^(a)C(O)R^(a), NR^(a)C(O)OR^(a),NR^(a)C(O)NR^(a)R^(a), C(═NR^(a))R^(a), C(═NR^(a))NR^(a)R^(a),NR^(a)C(═NR^(a))NR^(a)R^(a), NR^(a)S(O)R^(a), NR^(a)S(O)₂R^(a),NR^(a)S(O)₂NR^(a)R^(a), S(O)R^(a), S(O)NR^(a)R^(a), S(O)₂R^(a), orS(O)₂NR^(a)R^(a), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, are independently optionally substitutedwith 1, 2, 3, or 4 R^(b) substituents;R^(a) is selected from hydrogen, cyano, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, or(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are independentlyoptionally substituted with 1, 2, 3, 4, or 5 R^(d) substituents;R^(b) is selected from halo, hydroxy, cyano, amino, nitro, C₁₋₄ alkyl,C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, NHOR^(c), OR^(c), SR^(c), C(O)R^(c),C(O)NR^(c)R^(c), C(O)OR^(c), OC(O)R^(c), OC(O)NR^(c)R^(c),C(═NR^(c))NR^(c)R^(c), NR^(c)C(═NR^(c))NR^(c)R^(c), NHR^(c),NR^(c)R^(c), NR^(c)C(O)R^(c), NR^(c)C(O)OR^(c), NR^(c)C(O)NR^(c)R^(c),NR^(c)S(O)R^(c), NR^(c)S(O)₂R^(c), NR^(c)S(O)₂NR^(c)R^(c), S(O)R^(c),S(O)NR^(c)R^(c), S(O)₂R^(c) or S(O)₂NR^(c)R^(c); wherein the C₁₋₄ alkyl,C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- are optionally substituted with 1, 2, or 3R^(d) substituents;R^(d) is selected from cyano, amino, C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo,C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, NHOR^(e), OR^(e), SR^(e), C(O)R^(e),C(O)NR^(e)R^(e), C(O)OR^(e), OC(O)R^(e), OC(O)NR^(e)R^(e), NHR^(e),NR^(e)R^(e), NR^(e)C(O)R^(e), NR^(e)C(O)NR^(e)R^(e), NR^(e)C(O)OR^(e),C(═NR^(e))NR^(e)R^(e), NR^(e)C(═NR^(e))NR^(e)R^(e),NR^(e)C(═NOH)NR^(e)R^(e), NR^(e)C(═NCN)NR^(e)R^(e), S(O)R^(e),S(O)NR^(e)R^(e), S(O)₂R^(e), NR^(e)S(O)₂R^(e), NR^(e)S(O)₂NR^(e)R^(e),or S(O)₂NR^(e)R^(e), wherein the C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- are optionally substituted with 1, 2, or 3R^(f) substituents;R^(e) is selected from hydrogen, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, or(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are optionally substitutedwith 1, 2, 3, 4, or 5 R^(f) substituent;R^(f) is selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, halogen, CN, NHOR^(g), OR^(g), SR^(g),C(O)R^(g), C(O)NR^(g)R^(g), C(O)OR^(g), OC(O)R^(g), OC(O)NR^(g)R^(g),NHR^(g), NR^(g)R^(g), NR^(g)C(O)R^(g), NR^(g)C(O)NR^(g)R^(g),NR^(g)C(O)OR^(g), C(═NR^(g))NR^(g)R^(g), NR^(g)C(═NR^(g))NR^(g)R^(g),S(O)R^(g), S(O)NR^(g)R^(g), S(O)₂R^(g), NR^(g)S(O)₂R^(g),NR^(g)S(O)₂NR^(g)R^(g), or S(O)₂NR^(g)R^(g); wherein the C₁₋₄ alkyl,C₁₋₄haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄alkyl- are optionally substituted with 1, 2, 3, 4, or 5 R^(n)substituents;R^(n) is selected from cyano, halo, C₁_₄ alkyl, C₃₋₁₀ cycloalkyl, 4-7membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-6 memberedheteroaryl)-C₁₋₄ alkyl-, (4-7 membered heterocycloalkyl)-C₁₋₄ alkyl-,C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl, R^(o),NHOR^(o), OR^(o), SR^(o), C(O)R^(o), C(O)NR^(o)R^(o), C(O)OR^(o),OC(O)R^(o), OC(O)NR^(o)R^(o), NHR^(o), NR^(o)R^(o), NR^(o)C(O)R^(o),NR^(o)C(O)NR^(o)R^(o), NR^(o)C(O)OR^(o), C(═NR)NR^(o)R^(o),NR^(o)C(═NR^(o))NR^(o)R^(o), S(O)R^(o), S(O)NR^(o)R^(o), S(O)₂R^(o),NR^(o)S(O)₂R^(o), NR^(o)S(O)₂NR^(o)R^(o), or S(O)₂NR^(o)R^(o), whereinthe C₁₋₄ alkyl, C₃₋₁₀ cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀aryl, 5-6 membered heteroaryl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-6 membered heteroaryl)-C₁₋₄ alkyl-, (4-7membered heterocycloalkyl)-C₁₋₄ alkyl-, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl,C₂₋₆ alkynyl and C₁₋₄haloalkyl are optionally substituted with 1, 2 or 3R^(q) substituents;R^(g) is selected from hydrogen, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, or(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are optionally substitutedwith 1, 2, or 3 R^(p) substituents;R^(p) is selected from halo, cyano, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-,NHOR^(r), OR^(r), SR^(r), C(O)R^(r), C(O)NR^(r)R^(r), C(O)OR^(r),OC(O)R^(r), OC(O)NR^(r)R^(r), NHR^(r), NR^(r)R^(r), NR^(r)C(O)R^(r),NR^(r)C(O)NR^(r)R^(r), NR^(r)C(O)OR^(r), C(═NR^(r))NR^(r)R^(r),NR^(r)C(═NR^(r))NR^(r)R^(r), NR^(r)C(═NOH)NR^(r)R^(r),NR^(r)C(═NCN)NR^(r)R^(r), S(O)R^(r), S(O)NR^(r)R^(r), S(O)₂R^(r),NR^(r)S(O)₂R^(r), NR^(r)S(O)₂NR^(r)R^(r) or S(O)₂NR^(r)R^(r), whereinthe C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- are optionally substituted with 1, 2 or 3R^(q) substituents;R^(e), R^(i), R^(k), R^(o) and R^(r) are independently selected fromhydrogen, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5 or 6-memberedheteroaryl, 4-6 membered heterocycloalkyl, C₁₋₄ haloalkyl, C₂₋₄ alkenyl,or C₂₋₄ alkynyl, wherein the C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5or 6-membered heteroaryl, 4-6 membered heterocycloalkyl, C₂₋₄ alkenyl,and C₂₋₄ alkynyl are optionally substituted with 1, 2 or 3 R^(q)substituents;R^(q) is selected from hydroxy, cyano, amino, halo, COOH, C₁₋₆haloalkyl, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylthio, C₅₋₆ aryl, 5-6membered heteroaryl, 4-6 membered heterocycloalkyl, C₃₋₆ cycloalkyl,NHR⁸, NR⁸R⁸, and C₁₋₄ haloalkoxy, wherein the C₁₋₆ alkyl, C₅₋₆ aryl,C₃₋₆ cycloalkyl, 4-6 membered heterocycloalkyl, and 5-6 memberedheteroaryl are optionally substituted with halo, hydroxy, cyano, COOH,amino, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₅₋₆aryl, C₃₋₁₀ cycloalkyl, 5-6 membered heteroaryl and 4-6 memberedheterocycloalkyl;R⁸ is C₁₋₆ alkyl.

The present disclosure further describes the process of preparation ofcompounds of Formula I, Formula II, Formula III, Formula IV, Formula V,Formula VI, or their polymorphs, stereoisomers, tautomers, prodrugs,solvates, and pharmaceutically acceptable salts thereof.

The present disclosure also discloses the method for the treatmentand/or prevention of various diseases, including cancer and infectiousdiseases, comprising administering to a subject suffering from theproliferative disorder or cancer a therapeutically effective amount ofthe compound of Formula I, Formula II, Formula III, Formula IV, FormulaV, Formula VI, or the pharmaceutical composition comprising compound ofFormula I, Formula II, Formula III, Formula IV, Formula V, or FormulaVI, with other clinically relevant cytotoxic agents or non-cytotoxicagents to a subject in need thereof.

The present disclosure further discloses the use of the compounds ofFormula I, Formula II, Formula III, Formula IV, Formula V, Formula VI,or the pharmaceutical composition comprising compounds of Formula I,Formula II, Formula III, Formula IV, Formula V, or Formula VI, for thetreatment and/or prevention of various diseases including proliferativedisorder or cancer; or treatment of cancer together with otherclinically relevant cytotoxic agents or non-cytotoxic agents.

The present disclosure also discloses a method for the treatment ofcancer, said method comprising administering a combination of thecompounds of Formula I, Formula II, Formula III, Formula IV, Formula V,Formula VI, or the pharmaceutical composition comprising compounds ofFormula I, Formula II, Formula III, Formula IV, Formula V, or FormulaVI, with other clinically relevant cytotoxic agents or non-cytotoxicagents to a subject in need thereof.

The present disclosure further describes a method of treatment ofcancer, said method comprising administering a combination of thecompounds of Formula I, Formula II, Formula III, Formula IV, Formula V,Formula VI, or the pharmaceutical composition, with other clinicallyrelevant immune modulators agents to a subject in need of thereof.

These and other features, aspects, and advantages of the present subjectmatter will become better understood with reference to the followingdescription. This summary is provided to introduce a selection ofconcepts in a simplified form. This summary is not intended to identifykey features or essential features of the disclosure, nor is it intendedto be used to limit the scope of the subject matter.

DETAILED DESCRIPTION

Those skilled in the art will be aware that the present disclosure issubject to variations and modifications other than those specificallydescribed. It is to be understood that the present disclosure includesall such variations and modifications. The disclosure also includes allsuch steps, features, compositions and compounds referred to orindicated in this specification, individually or collectively, and anyand all combinations of any or more of such steps or features.

Definitions

For convenience, before further description of the present disclosure,certain terms employed in the specification, and examples are collectedhere. These definitions should be read in the light of the remainder ofthe disclosure and understood as by a person of skill in the art. Theterms used herein have the meanings recognized and known to those ofskill in the art, however, for convenience and completeness, particularterms and their meanings are set forth below.

The articles “a”, “an” and “the” are used to refer to one or to morethan one (i.e., to at least one) of the grammatical object of thearticle.

Throughout the description and the claims which follow, unless thecontext requires otherwise, the word “comprise”, and variations such as“comprises” and “comprising”, will be understood to imply the inclusionof a stated integer or step or group of integers but not to theexclusion of any other integer or step or group of integers or steps.

The term “including” is used to mean “including but not limited to”.“Including” and “including but not limited to” are used interchangeably.

In the structural formulae given herein and throughout the presentdisclosure, the following terms have been indicated meaning, unlessspecifically stated otherwise.

Furthermore, the compound of Formula I, Formula II, Formula III, FormulaIV, Formula V, Formula VI, can be its derivatives, analogs,stereoisomers, diastereomers, geometrical isomers, polymorphs, solvates,co-crystals, intermediates, metabolites, prodrugs or pharmaceuticallyacceptable salts and compositions.

The compounds of Formula I, Formula II, Formula III, Formula IV, FormulaV, Formula VI, and their polymorphs, stereoisomers, prodrugs, solvates,co-crystals, intermediates, pharmaceutically acceptable salts, andmetabolites thereof can also be referred as “compounds of the presentdisclosure”.

The compounds according to Formula I, Formula II, Formula III, FormulaIV, Formula V, Formula VI, may contain one or more asymmetric centers(also referred to as a chiral centers) and may, therefore, exist asindividual enantiomers, diastereoisomers, or other stereoisomeric forms,or as mixtures thereof. Chiral centers, such as chiral carbon atoms, mayalso be present in a substituent such as an alkyl group. Where thestereochemistry of a chiral center present in Formula I, Formula II,Formula III, Formula IV, Formula V, Formula VI, or in any chemicalstructure illustrated herein, is not specified, the structure isintended to encompass any stereoisomer and all mixtures thereof. Thus,compounds according to Formula I-VI containing one or more chiralcenters may be used as racemic modifications including racemic mixturesand racemates, enantiomerically-enriched mixtures, or asenantiomerically-pure individual stereoisomers.

Compounds disclosed herein include isotopes of hydrogen, carbon, oxygen,fluorine, chlorine, iodine and sulfur which can be incorporated into thecompounds, such as not limited to ²H (D), ³H (T), c ¹¹C, ¹³C, ¹⁴C, ¹⁵N,¹⁸F, ³⁵S, ³⁶Cl and ¹²⁵I. Compounds of this invention where in atoms wereisotopically labeled for example radioisotopes such as ³H, ¹³C, ¹⁴C, andthe like can be used in metabolic studies and kinetic studies. Compoundsof the invention where hydrogen is replaced with deuterium may improvethe metabolic stability and pharmacokinetics properties of the drug suchas in vivo half life.

Individual stereoisomers of a compound according to Formula I-VI whichcontain one or more asymmetric centers may be resolved by methods knownto those skilled in the art. For example, such resolution may be carriedout (1) by formation of diastereoisomeric salts, complexes or otherderivatives; (2) by selective reaction with a stereoisomer-specificreagent, for example by enzymatic oxidation or reduction; or (3) bygas-liquid or liquid chromatography in a chiral environment, forexample, on a chiral support such as silica with a bound chiral ligandor in the presence of a chiral solvent. It will be appreciated thatwhere the desired stereoisomer is converted into another chemical entityby one of the separation procedures described above, a further step isrequired to liberate the desired form.

Alternatively, specific stereoisomers may be synthesized by asymmetricsynthesis using optically active reagents, substrates, catalysts orsolvents, or by converting one enantiomer to the other by asymmetrictransformation.

It is to be understood that the references herein to compounds ofFormula I-VI and salts thereof covers the compounds of Formula I-VI asfree bases, or as salts thereof, for example as pharmaceuticallyacceptable salts thereof. Thus, in one embodiment, the invention isdirected to compounds of Formula I-VI as the free base. In anotherembodiment, the invention is directed to compounds of Formula I-VI andsalts thereof. In a further embodiment, the invention is directed tocompounds of Formula I-VI and pharmaceutically acceptable salts thereof.

It will be appreciated that pharmaceutically acceptable salts of thecompounds according to Formula I, Formula II, Formula III, Formula IV,Formula V, or Formula VI, may be prepared. Indeed, in certainembodiments of the invention, pharmaceutically acceptable salts of thecompounds according to Formula I-VI may be preferred over the respectivefree base because such salts impart greater stability or solubility tothe molecule thereby facilitating formulation into a dosage form.Accordingly, the invention is further directed to compounds of FormulaI-VI, and pharmaceutically acceptable salts thereof.

Included within the scope of the “compounds of the invention” are allsolvates (including hydrates), complexes, polymorphs, prodrugs,radiolabelled derivatives, and stereoisomers of the compounds of FormulaI-VI, and salts thereof.

The compounds of the invention may exist in solid or liquid form. In thesolid state, the compounds of the invention may exist in crystalline ornon-crystalline form, or as a mixture thereof. For compounds of theinvention that are in crystalline form, the skilled artisan willappreciate that pharmaceutically acceptable solvates may be formedwherein solvent molecules are incorporated into the crystalline latticeduring crystallization. Solvates may involve non-aqueous solvents suchas ethanol, isopropyl alcohol, dimethylsulfoxide (DMSO), acetic acid,ethanolamine, and ethyl acetate, or they may involve water as thesolvent that is incorporated into the crystalline lattice. Solvateswherein water is the solvent that is incorporated into the crystallinelattice are typically referred to as “hydrates”. Hydrates includestoichiometric hydrates as well as compositions containing variableamounts of water. The invention includes all such solvates.

It will be further appreciated that certain compounds of the inventionthat exist in crystalline form, including the various solvates thereof,may exhibit polymorphism (i.e. the capacity to occur in differentcrystalline structures). These different crystalline forms are typicallyknown as “polymorphs”. The invention includes such polymorphs.Polymorphs have the same chemical composition but differ in packing,geometrical arrangement, and other descriptive properties of thecrystalline solid state. Polymorphs, therefore, may have differentphysical properties such as shape, density, hardness, deformability,stability, and dissolution properties. Polymorphs typically exhibitdifferent melting points, IR spectra, and X-ray powder diffractionpatterns, which may be used for identification. It will be appreciatedthat different polymorphs may be produced, for example, by changing oradjusting the reaction conditions or reagents, used in making thecompound. For example, changes in temperature, pressure, or solvent mayresult in polymorphs. In addition, one polymorph may spontaneouslyconvert to another polymorph under certain conditions. The term“polymorphs” refers to crystal forms of the same molecule, and differentpolymorphs may have different physical properties such as, for example,melting temperatures, heats of fusion, solubilities, dissolution ratesand/or vibrational spectra as a result of the arrangement orconformation of the molecules in the crystal lattice.

The term “substituted” in reference to a group indicates that a hydrogenatom attached to a member atom within a group is replaced. It should beunderstood that the term “substituted” includes the implicit provisionthat such substitution be in accordance with the permitted valence ofthe substituted atom and the substituent and that the substitutionresults in a stable compound (i.e. one that does not spontaneouslyundergo transformation such as rearrangement, cyclisation, orelimination). In certain embodiments, a single atom may be substitutedwith more than one substituent as long as such substitution is inaccordance with the permitted valence of the atom. Suitable substituentsare defined herein for each substituted or optionally substituted group.

The term “prodrugs” refers to the precursor of the compound of FormulaIa, and Formula I which on administration undergoes chemical conversionby metabolic processes before becoming active pharmacologicalsubstances. In general, such prodrugs will be functional derivatives ofa compound of the invention, which are readily convertible in vivo intoa compound of the invention.

The term “alkyl” refers to a saturated hydrocarbon chain having thespecified number of carbon atoms. For example, which are not limited,C₁₋₆ alkyl refers to an alkyl group having from 1-6 carbon atoms, or 1-4carbon atoms. Alkyl groups may be straight or branched chained groups.Representative branched alkyl groups have one, two, or three branches.Preferred alkyl groups include, without limitation, methyl, ethyl,n-propyl, isopropyl, butyl, isobutyl, and t-butyl.

The term “alkoxy” refers to an alkyl group attached via an oxygenlinkage to the rest of the molecule. For example, C₁₋₆ alkoxy refers toan alkyl group having from 1-6 carbon atoms, or 1-4 carbon atomsattached via an oxygen linkage to the rest of the molecule. Preferredalkoxy groups include, without limitation, —OCH₃ (methoxy), —OC₂H₅(ethoxy) and the like.

The term “haloalkyl” refers to a halogen in an alkyl group as definedabove attached via alkyl linkage to the rest of the molecule. Forexample, C₁₋₆ haloalkyl refers to an alkyl group having from 1-6 carbonatoms, or 1-4 carbon atoms wherein one or more hydrogen atoms arereplaced by the same number of identical or different halogen atoms.Preferred haloalkyl groups include, without limitation, —CH2Cl, —CHCl2,trifluoromethyl, 2,2,2-trifluoroethyl, and the like.

The term “haloalkoxy” refers to a halogen in an alkoxy group as definedabove further attached via oxygen linkage to the rest of the molecule.For example, C₁₋₆ haloalkoxy refers to an alkoxy group having from 1-6carbon atoms, or 1-3 carbon atoms further attached via halo linkage.Preferred haloalkoxy groups include, without limitation, —OCH₂Cl,—OCHCl₂, and the like.

The term “halo” or “halogen” refers to a halogen radical, for example,fluoro, chloro, bromo, or iodo.

The term “cycloalkyl” refers to a saturated hydrocarbon ring having aspecified number of carbon atoms, which may be monocyclic or polycyclic.For example, which are not limited, C₃₋₁₀ cycloalkyl refers to acycloalkyl group having from 3 to 10 member atoms or 3 to 6 memberatoms. The polycyclic ring denotes hydrocarbon systems containing two ormore ring systems with one or more ring carbon atoms in common i.e. aspiro, fused or bridged structures. For example, which are not limited,C₃₋₆ cycloalkyl refers to a cycloalkyl group having from 3 to 6 memberedatoms. Preferred cycloalkyl groups include, without limitation,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctanyl,perhydronaphthyl, adamantyl, noradamantyl and norbornyl groups, bridgedcyclic groups or spirobicyclic groups e.g spiro [4.4] non-2-yl, and thelike.

The term “aryl” refers to aromatic ring having a specified number ofcarbon atoms. For example, C₅₋₆ aryl refers to an aryl group having 5 or6 member atoms, or 6 member atoms. C₆₋₁₀ aryl refers to an aryl grouphaving 6 to 10 member atoms. Preferred aryl groups include, withoutlimitation, phenyl, and the like.

The term “heteroaryl” refers to aromatic rings containing from 1 to 3heteroatoms in the ring. “Heteroaryl” groups may be substituted with oneor one or more substituents if so defined herein. The “C₁₋₆ heteroaryl”rings having 1 or 6 carbon as member atoms. The term “5-14 memberedheteroaryl” has 5 to 14 carbon as member atoms. The “heteroaryl”includes pyridinyl, tetrazolyl and pyrazolyl. “Heteroatom” refers to anitrogen, sulfur, or oxygen atom, for example a nitrogen atom or anoxygen atom.

The term “heterocyclic” or refer to saturated or unsaturated monocyclicaliphatic rings containing 5, 6, or 7 ring members including 1-3heteroatoms or to saturated or unsaturated bicyclic, tricyclic,tetracyclic aliphatic rings containing 5, 6 or 7 ring members including1-3 heteroatoms, which may include spiro, fused, or bridged ringsystems. In certain embodiments, “heterocyclic” groups are saturated. Inother embodiments, “heterocyclic” groups are unsaturated. “heterocyclic”groups containing more than one heteroatom may contain differentheteroatoms. “heterocyclic” groups may be substituted with one or moresubstituents as defined herein. “heterocyclic” includes piperidinyl,tetrahydropyranyl, azepinyl, oxazepinyl, azabicyclo[3.1.0]hexanyl.

The term “heterocycloalkyl-” refers to to a heterocyclic group asdefined above further attached via alkyl linkage to the rest of themolecule. For example, 4-10 membered heterocycloalkyl refers toheterocyclic group as defined above further attached via alkyl linkageto the rest of the molecule.

The phrase “pharmaceutically acceptable” refers to those compounds,materials, compositions, and dosage forms which are, within the scope ofsound medical judgment, suitable for use in contact with the tissues ofhuman beings and animals without excessive toxicity, irritation, orother problem or complication, commensurate with a reasonablebenefit/risk ratio.

As used herein, the term “pharmaceutically acceptable salts” refers tosalts that retain the desired biological activity of the subjectcompound and exhibit minimal undesired toxicological effects. Thesepharmaceutically acceptable salts may be prepared in situ during thefinal isolation and purification of the compound, or by separatelyreacting the purified compound in its free base form with a suitableacid.

Salts and solvates having non-pharmaceutically acceptable counter-ionsor associated solvents are within the scope of the present invention,for example, for use as intermediates in the preparation of othercompounds of Formula I, Formula II, Formula III, Formula IV, Formula V,Formula VI, and their pharmaceutically acceptable salts.

Thus, one embodiment of the invention embraces compounds of Formula I,Formula II, Formula III, Formula IV, Formula V, Formula VI, and saltsthereof. Compounds according to and Formula I, Formula II, Formula III,Formula IV, Formula V, Formula VI contain a basic functional group andare therefore capable of forming pharmaceutically acceptable acidaddition salts by treatment with a suitable acid. Suitable acids includepharmaceutically acceptable inorganic acids and pharmaceuticallyacceptable organic acids. Representative pharmaceutically acceptableacid addition salts include hydrochloride, hydrobromide, nitrate,methylnitrate, sulfate, bisulfate, sulfamate, phosphate, acetate,hydroxyacetate, phenyl acetate, propionate, butyrate, iso-butyrate,valerate, maleate, hydroxymaleate, acrylate, fumarate, malate, tartrate,citrate, salicylate, glycollate, lactate, heptanoate, phthalate,oxalate, succinate, benzoate, o-acetoxybenzoate, chlorobenzoate,methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate,naphthoate, hydroxynaphthoate, mandelate, tannate, formate, stearate,ascorbate, palmitate, oleate, pyruvate, pamoate, malonate, laurate,glutarate, glutamate, estolate, methanesulfonate (mesylate),ethanesulfonate (esylate), 2-hydroxyethanesulfonate, benzenesulfonate(besylate), aminobenzenesulfonate, p-toluenesulfonate (tosylate), andnaphthalene-2-sulfonate.

The term “PD-1/PD-L1 inhibitor or inhibitory compounds” or “inhibitorsof PD-1/PD-L1 activation” is used to identify a compound, which iscapable of blocking PD-1/PD-L1 pathway to prevent inhibitory signallingfrom cancer cells and enabling CTLs to elicit an immune response againstthe target/cancer cells and thus treat cancer and other diseases orconditions associated with activation of PD1/PD-L1.

The term “cytotoxic agents” or “inhibitors” is used to identify anyagents or drugs which are capable of killing cells including cancercells. These agents or 10 inhibitors may stop cancer cells from growingand dividing and may cause tumors to shrink in size.

The term “non-cytotoxic agents” or “inhibitors” is used to identify anyagents or inhibitors are which does not directly kill cells, but insteadaffects cellular transport and metabolic functions to ultimately producecell death.

The term “immune checkpoint inhibitors agents” or “immune modulatorsagents” are used to identify any agents or inhibitors that blockscertain proteins made by some types of immune system cells, such as Tcells, and some cancer cells. These proteins help keep immune responsesin check and can keep T cells from killing cancer cells.

When these proteins are blocked, the “brakes” on the immune system arereleased 20 and T cells are able to kill cancer cells better. The immunecheckpoint inhibitors include inhibitors against immune checkpointmolecules such as CD27, CD28, CD40, CD122, CD96, CD73, CD47, OX40, GITR,CSF1R, JAK, PI3K delta, PI3K gamma, TAM, arginase, CD137 (also known as4-1B), ICOS, A2AR, B7-H3, B7-H4, BTLA, CTLA-4, LAG3, TIM3, VISTA, PD-1,PD-L1 and PD-L2. The terms “immune modulators agents” and “immunecheckpoint inhibitors” are used interchangeably throughout the presentdisclosure.

As discussed in the background section, the identification anddevelopment of new PD-1/PD-L1 inhibitor compounds treating cancer andother diseases or conditions associated with activation of PD-1/PD-L1would open new opportunities in the realm of cancer treatment.

A term once described, the same meaning applies for it, throughout thedisclosure.

In an embodiment of the present disclosure, there is provided a compoundof Formula I

their polymorphs, stereoisomers, tautomers, prodrugs, solvates, andpharmaceutically acceptable salts thereof, wherein X₁ is selected from—CH₂O—, —OCH₂—, —C(O)NH— or —NHC(O)—; R₄ is selected from hydrogen,hydroxyl, C₁₋₆ alkyl, amino, —C(O)OR_(a1), C(O)NR_(b1)R_(c1), C₅₋₆ aryl,or C₁₋₆ heteroaryl, wherein C₁₋₆ alkyl is optionally substituted withone or more of the groups selected from the group consisting ofhydrogen, hydroxyl, amino, —C(O)OR_(a1), C(O)NR_(b1)R_(c1), C₅₋₆ aryl,and C₁₋₆ heteroaryl; R_(a1), R_(b1), and R_(c1) are independentlyselected from hydrogen or C₁₋₆ alkyl; X is selected from CR₃ or N; R₁,R₂, R₃, R₆, and R₇ are independently selected from hydrogen, halo, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a), SR^(a), NHOR^(a),C(O)R^(a), C(O)NR^(a)R^(a), C(O)OR^(a), OC(O)R^(a), OC(O)NR^(a)R^(a),NHR^(a), NR^(a)R^(a), NR^(a)C(O)R^(a), NR^(a)C(O)OR^(a),NR^(a)C(O)NR^(a)R^(a), C(═NR^(a))R^(a), C(═NR^(a))NR^(a)R^(a),NR^(a)C(═NR^(a))NR^(a)R^(a), NR^(a)S(O)R^(a), NR^(a)S(O)₂R^(a),NR^(a)S(O)₂NR^(a)R^(a), S(O)R^(a), S(O)NR^(a)R^(a), S(O)₂R^(a), orS(O)₂NR^(a)R^(a), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, are independently optionally substitutedwith 1, 2, 3, or 4 R^(b) substituents; R^(a) is selected from hydrogen,cyano, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, or (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10membered heterocycloalkyl)-C₁₋₄ alkyl- are independently optionallysubstituted with 1, 2, 3, 4, or 5 R^(d) substituents; R^(b) is selectedfrom halo, hydroxy, cyano, amino, nitro, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-,NHOR^(c), OR^(c), SR^(c), C(O)R^(c), C(O)NR^(c)R^(c), C(O)OR^(c),OC(O)R^(c), OC(O)NR^(c)R^(c), C(═NR^(c))NR^(c)R^(c),NR^(c)C(═NR^(c))NR^(c)R^(c), NHR^(c), NR^(c)R^(c), NR^(c)C(O)R^(c),NR^(c)C(O)OR^(c), NR^(c)C(O)NR^(c)R^(c), NR^(c)S(O)R^(c),NR^(c)S(O)₂R^(c), NR^(c)S(O)₂NR^(c)R^(c), S(O)R^(c), S(O)NR^(c)R^(c),S(O)₂R^(c) or S(O)₂NR^(c)R^(c); wherein the C₁₋₄ alkyl, C₂₋₄ alkenyl,C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-are optionally substituted with 1, 2, or 3 R^(d) substituents; R^(c) isselected from hydrogen, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, or (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10membered heterocycloalkyl)-C₁₋₄ alkyl- are optionally substituted with1, 2, 3, 4, or 5 R^(f) substituent;R^(d) is selected from cyano, amino, C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo,C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, NHOR^(e), OR^(e), SR^(e), C(O)R^(e),C(O)NR^(e)R^(e), C(O)OR^(e), OC(O)R^(e), OC(O)NR^(e)R^(e), NHR^(e),NR^(e)R^(e), NR^(e)C(O)R^(e), NR^(e)C(O)NR^(e)R^(e), NR^(e)C(O)OR^(e),C(═NR^(e))NR^(e)R^(e), NR^(e)C(═NR^(e))NR^(e)R^(e),NR^(e)C(═NOH)NR^(e)R^(e), NR^(e)C(═NCN)NR^(e)R^(e), S(O)R^(e),S(O)NR^(e)R^(e), S(O)₂R^(e), NR^(e)S(O)₂R^(e), NR^(e)S(O)₂NR^(e)R^(e),or S(O)₂NR^(e)R^(e), wherein the C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- are optionally substituted with 1, 2, or 3R^(f) substituents;R^(f) is selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, halogen, CN, NHOR^(g), OR^(g), SR^(g),C(O)R^(g), C(O)NR^(g)R^(g), C(O)OR^(g), OC(O)R^(g), OC(O)NR^(g)R^(g),NHR^(g), NR^(g)R^(g), NR^(g)C(O)R^(g), NR^(g)C(O)NR^(g)R^(g),NR^(g)C(O)OR^(g), C(═NR^(g))NR^(g)R^(g), NR^(g)C(═NR^(g))NR^(g)R^(g),S(O)R^(g), S(O)NR^(g)R^(g), S(O)₂R^(g), NR^(g)S(O)₂R^(g),NR^(g)S(O)₂NR^(g)R^(g), or S(O)₂NR^(g)R^(g); wherein the C₁₋₄ alkyl,C₁₋₄haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄alkyl- are optionally substituted with 1, 2, 3, 4, or 5 R^(n)substituents; R^(g) is selected from hydrogen, C₁₋₆ alkyl, C₁₋₄haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, or (4-10 membered heterocycloalkyl)-C₁₋₄alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- are optionally substituted with 1, 2, or 3R^(p) substituents; R^(n) is selected from cyano, halo, C₁₋₄ alkyl,C₃₋₁₀ cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6membered heteroaryl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄alkyl-, (5-6 membered heteroaryl)-C₁₋₄ alkyl-, (4-7 memberedheterocycloalkyl)-C₁₋₄ alkyl-, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₄ haloalkyl, R^(o), NHOR^(o), OR^(o), SR^(o), C(O)R^(o),C(O)NR^(o)R^(o), C(O)OR^(o), OC(O)R^(o), OC(O)NR^(o)R^(o), NHR^(o),NR^(o)R^(o), NR^(o)C(O)R^(o), NR^(o)C(O)NR^(o)R^(o), NR^(o)C(O)OR^(o),C(═NR)NR^(o)R^(o), NR^(o)C(═NR^(o))NR^(o)R^(o), S(O)R^(o),S(O)NR^(o)R^(o), S(O)₂R^(o), NR^(o)S(O)₂R^(o), NR^(o)S(O)₂NR^(o)R^(o),or S(O)₂NR^(o)R^(o), wherein the C₁₋₄ alkyl, C₃₋₁₀ cycloalkyl, 4-7membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-6 memberedheteroaryl)-C₁₋₄ alkyl-, (4-7 membered heterocycloalkyl)-C₁₋₄ alkyl-,C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₄haloalkyl areoptionally substituted with 1, 2 or 3 R^(q) substituents; R^(p) isselected from halo, cyano, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, NHOR^(r), OR^(r), SR^(r),C(O)R^(r), C(O)NR^(r)R^(r), C(O)OR^(r), OC(O)R^(r), OC(O)NR^(r)R^(r),NHR^(r), NR^(r)R^(r), NR^(r)C(O)R^(r), NR^(r)C(O)NR^(r)R^(r),NR^(r)C(O)OR^(r), C(═NR^(r))NR^(r)R^(r), NR^(r)C(═NR^(r))NR^(r)R^(r),NR^(r)C(═NOH)NR^(r)R^(r), NR^(r)C(═NCN)NR^(r)R^(r), S(O)R^(r),S(O)NR^(r)R^(r), S(O)₂R^(r), NR^(r)S(O)₂R^(r), NR^(r)S(O)₂NR^(r)R^(r) orS(O)₂NR^(r)R^(r), wherein the C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-are optionally substituted with 1, 2 or 3 R^(q) substituents; R^(e),R^(i), R^(k), R^(o) and R^(r) are independently selected from hydrogen,C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5 or 6-membered heteroaryl, 4-6membered heterocycloalkyl, C₁₋₄ haloalkyl, C₂₋₄ alkenyl, or C₂₋₄alkynyl, wherein the C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5 or6-membered heteroaryl, 4-6 membered heterocycloalkyl, C₂₋₄ alkenyl, andC₂₋₄ alkynyl are optionally substituted with 1, 2 or 3 R^(q)substituents; R^(q) is selected from hydroxy, cyano, amino, halo, COOH,C₁₋₆ haloalkyl, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylthio, C₅₋₆ aryl, 5-6membered heteroaryl, 4-6 membered heterocycloalkyl, C₃₋₆ cycloalkyl,NHR⁸, NR⁸R⁸, and C₁₋₄ haloalkoxy, wherein the C₁₋₆ alkyl, C₅₋₆ aryl,C₃₋₆ cycloalkyl, 4-6 membered heterocycloalkyl, and 5-6 memberedheteroaryl are optionally substituted with halo, hydroxy, cyano, COOH,amino, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₅₋₆aryl, C₃₋₁₀ cycloalkyl, 5-6 membered heteroaryl and 4-6 memberedheterocycloalkyl; R⁸ is C₁₋₆ alkyl; m is 1 or 2; Ring A is selected fromsubstituted or unsubstituted C₅₋₁₀ aryl, substituted or unsubstitutedC₃₋₆ cycloalkyl, and substituted or unsubstituted 5-10 memberedmonocyclic or bicyclic saturated or unsaturated heterocyclic ring with1-3 heteroatoms selected from N, S or O; Ring B is selected from C₅₋₁₀aryl, C₃₋₆ cycloalkyl, 5-10 membered monocyclic or bicyclic saturated orunsaturated heterocyclic ring with 1-3 heteroatoms selected from N, S orO.

In an embodiment of the present disclosure, there is provided a compoundof Formula I, their polymorphs, stereoisomers, tautomers, prodrugs,solvates, and pharmaceutically acceptable salts thereof, wherein X₁ isselected from —CH₂O—, —OCH₂—, —C(O)NH— or —NHC(O)—; R₄ is selected fromhydrogen, hydroxyl, C₁₋₆ alkyl, amino, —C(O)OR_(a1), C(O)NR_(b1)R_(c1),C₅₋₆ aryl, or C₁₋₆ heteroaryl, wherein C₁₋₆ alkyl is optionallysubstituted with one or more of the groups selected from the groupconsisting of hydrogen, hydroxyl, amino, —C(O)OR_(a1),C(O)NR_(b1)R_(c1), C₅₋₆ aryl, and C₁₋₆ heteroaryl; R_(a1), R_(b1), andR_(c1) are independently selected from hydrogen or C₁₋₆ alkyl; X is CR₃;R₁, R₂, R₃, R₆, and R₇ are independently selected from hydrogen, halo,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a), SR^(a), NHOR^(a),C(O)R^(a), C(O)NR^(a)R^(a), C(O)OR^(a), OC(O)R^(a), OC(O)NR^(a)R^(a),NHR^(a), NR^(a)R^(a), NR^(a)C(O)R^(a), NR^(a)C(O)OR^(a),NR^(a)C(O)NR^(a)R^(a), C(═NR^(a))R^(a), C(═NR^(a))NR^(a)R^(a),NR^(a)C(═NR^(a))NR^(a)R^(a), NR^(a)S(O)R^(a), NR^(a)S(O)₂R^(a),NR^(a)S(O)₂NR^(a)R^(a), S(O)R^(a), S(O)NR^(a)R^(a), S(O)₂R^(a), orS(O)₂NR^(a)R^(a), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, are independently optionally substitutedwith 1, 2, 3, or 4 R^(b) substituents; R^(a) is selected from hydrogen,cyano, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, or (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10membered heterocycloalkyl)-C₁₋₄ alkyl- are independently optionallysubstituted with 1, 2, 3, 4, or 5 R^(d) substituents; R^(b) is selectedfrom halo, hydroxy, cyano, amino, nitro, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-,NHOR^(c), OR^(c), SR^(c), C(O)R^(c), C(O)NR^(c)R^(c), C(O)OR^(c),OC(O)R^(c), OC(O)NR^(c)R^(c), C(═NR^(c))NR^(c)R^(c),NR^(c)C(═NR^(c))NR^(c)R^(c), NHR^(c), NR^(c)R^(c), NR^(c)C(O)R^(c),NR^(c)C(O)OR^(c), NR^(c)C(O)NR^(c)R^(c), NR^(c)S(O)R^(c),NR^(c)S(O)₂R^(c), NR^(c)S(O)₂NR^(c)R^(c), S(O)R^(c), S(O)NR^(c)R^(c),S(O)₂R^(c) or S(O)₂NR^(c)R^(c); wherein the C₁₋₄ alkyl, C₂₋₄ alkenyl,C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-are optionally substituted with 1, 2, or 3 R^(d) substituents; R^(c) isselected from hydrogen, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, or (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10membered heterocycloalkyl)-C₁₋₄ alkyl- are optionally substituted with1, 2, 3, 4, or 5 R^(f) substituent;

R^(d) is selected from cyano, amino, C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo,C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, NHOR^(e), OR^(e), SR^(e), C(O)R^(e),C(O)NR^(e)R^(e), C(O)OR^(e), OC(O)R^(e), OC(O)NR^(e)R^(e), NHR^(e),NR^(e)R^(e), NR^(e)C(O)R^(e), NR^(e)C(O)NR^(e)R^(e), NR^(e)C(O)OR^(e),C(═NR^(e))NR^(e)R^(e), NR^(e)C(═NR^(e))NR^(e)R^(e),NR^(e)C(═NOH)NR^(e)R^(e), NR^(e)C(═NCN)NR^(e)R^(e), S(O)R^(e),S(O)NR^(e)R^(e), S(O)₂R^(e), NR^(e)S(O)₂R^(e), NR^(e)S(O)₂NR^(e)R^(e),or S(O)₂NR^(e)R^(e), wherein the C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- are optionally substituted with 1, 2, or 3R^(f) substituents; R^(f) is selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, halogen, CN, NHOR^(g),OR^(g), SR^(g), C(O)R^(g), C(O)NR^(g)R^(g), C(O)OR^(g), OC(O)R^(g),OC(O)NR^(g)R^(g), NHR^(g), NR^(g)R^(g), NR^(g)C(O)R^(g),NR^(g)C(O)NR^(g)R^(g), NR^(g)C(O)OR^(g), C(═NR^(g))NR^(g)R^(g),NR^(g)C(═NR^(g))NR^(g)R^(g), S(O)R^(g), S(O)NR^(g)R^(g), S(O)₂R^(g),NR^(g)S(O)₂R^(g), NR^(g)S(O)₂NR^(g)R^(g), or S(O)₂NR^(g)R^(g); whereinthe C₁₋₄ alkyl, C₁₋₄haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- are optionally substituted with 1, 2, 3,4, or 5 R^(n) substituents; R^(g) is selected from hydrogen, C₁₋₆ alkyl,C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, or (4-10 membered heterocycloalkyl)-C₁₋₄alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- are optionally substituted with 1, 2, or 3R^(p) substituents; R^(n) is selected from cyano, halo, C₁₋₄ alkyl,C₃₋₁₀ cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6membered heteroaryl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄alkyl-, (5-6 membered heteroaryl)-C₁₋₄ alkyl-, (4-7 memberedheterocycloalkyl)-C₁₋₄ alkyl-, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₄ haloalkyl, R^(o), NHOR^(o), OR^(o), SR^(o), C(O)R^(o),C(O)NR^(o)R^(o), C(O)OR^(o), OC(O)R^(o), OC(O)NR^(o)R^(o), NHR^(o),NR^(o)R^(o), NR^(o)C(O)R^(o), NR^(o)C(O)NR^(o)R^(o), NR^(o)C(O)OR^(o),C(═NR)NR^(o)R^(o), NR^(o)C(═NR^(o))NR^(o)R^(o), S(O)R^(o),S(O)NR^(o)R^(o), S(O)₂R^(o), NR^(o)S(O)₂R^(o), NR^(o)S(O)₂NR^(o)R^(o),or S(O)₂NR^(o)R^(o), wherein the C₁₋₄ alkyl, C₃₋₁₀ cycloalkyl, 4-7membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-6 memberedheteroaryl)-C₁₋₄ alkyl-, (4-7 membered heterocycloalkyl)-C₁₋₄ alkyl-,C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₄haloalkyl areoptionally substituted with 1, 2 or 3 R^(q) substituents; R^(p) isselected from halo, cyano, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, NHOR^(r), OR^(r), SR^(r),C(O)R^(r), C(O)NR^(r)R^(r), C(O)OR^(r), OC(O)R^(r), OC(O)NR^(r)R^(r),NHR^(r), NR^(r)R^(r), NR^(r)C(O)R^(r), NR^(r)C(O)NR^(r)R^(r),NR^(r)C(O)OR^(r), C(═NR^(r))NR^(r)R^(r), NR^(r)C(═NR^(r))NR^(r)R^(r),NR^(r)C(═NOH)NR^(r)R^(r), NR^(r)C(═NCN)NR^(r)R^(r), S(O)R^(r),S(O)NR^(r)R^(r), S(O)₂R^(r), NR^(r)S(O)₂R^(r), NR^(r)S(O)₂NR^(r)R^(r) orS(O)₂NR^(r)R^(r), wherein the C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-are optionally substituted with 1, 2 or 3 R^(q) substituents; R^(e),R^(i), R^(k), R^(o) and R^(r) are independently selected from hydrogen,C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5 or 6-membered heteroaryl, 4-6membered heterocycloalkyl, C₁₋₄ haloalkyl, C₂₋₄ alkenyl, or C₂₋₄alkynyl, wherein the C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5 or6-membered heteroaryl, 4-6 membered heterocycloalkyl, C₂₋₄ alkenyl, andC₂₋₄ alkynyl are optionally substituted with 1, 2 or 3 R^(q)substituents; R^(q) is selected from hydroxy, cyano, amino, halo, COOH,C₁₋₆ haloalkyl, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylthio, C₅₋₆ aryl, 5-6membered heteroaryl, 4-6 membered heterocycloalkyl, C₃₋₆ cycloalkyl,NHR⁸, NR⁸R⁸, and C₁₋₄ haloalkoxy, wherein the C₁₋₆ alkyl, C₅₋₆ aryl,C₃₋₆ cycloalkyl, 4-6 membered heterocycloalkyl, and 5-6 memberedheteroaryl are optionally substituted with halo, hydroxy, cyano, COOH,amino, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₅₋₆aryl, C₃₋₁₀ cycloalkyl, 5-6 membered heteroaryl and 4-6 memberedheterocycloalkyl; R⁸ is C₁₋₆ alkyl; m is 1 or 2; Ring A is selected fromsubstituted or unsubstituted C₅₋₁₀ aryl; Ring B is selected from C₅₋₁₀aryl, C₃₋₆ cycloalkyl, 5-10 membered monocyclic or bicyclic saturated orunsaturated heterocyclic ring with 1-3 heteroatoms selected from N, S orO.

In an embodiment of the present disclosure, there is provided a compoundof Formula II

their polymorphs, stereoisomers, tautomers, prodrugs, solvates, andpharmaceutically acceptable salts thereof, wherein X₁ is selected from—CH₂O—, —OCH₂—, —C(O)NH— or —NHC(O)—; R₄ is selected from hydrogen,hydroxyl, C₁₋₆ alkyl, amino, —C(O)OR_(a1), C(O)NR_(b1)R_(c1), C₅₋₆ aryl,or C₁₋₆ heteroaryl, wherein C₁₋₆ alkyl is optionally substituted withone or more of the groups selected from the group consisting ofhydrogen, hydroxyl, amino, —C(O)OR_(a1), C(O)NR_(b1)R_(c1), C₅₋₆ aryl,and C₁₋₆ heteroaryl; R_(a1), R_(b1), and R_(c1) are independentlyselected from hydrogen or C₁₋₆ alkyl; R₅ is selected from C₁₋₄ alkyl,cyano, or C₁₋₄ haloalkyl; R₁, R₂, R₃, R₆, and R₇ are independentlyselected from hydrogen, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-14 membered heteroaryl)-C₁₋₄alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a),SR^(a), NHOR^(a), C(O)R^(a), C(O)NR^(a)R^(a), C(O)OR^(a), OC(O)R^(a),OC(O)NR^(a)R^(a), NHR^(a), NR^(a)R^(a), NR^(a)C(O)R^(a),NR^(a)C(O)OR^(a), NR^(a)C(O)NR^(a)R^(a), C(═NR^(a))R^(a),C(═NR^(a))NR^(a)R^(a), NR^(a)C(═NR^(a))NR^(a)R^(a), NR^(a)S(O)R^(a),NR^(a)S(O)₂R^(a), NR^(a)S(O)₂NR^(a)R^(a), S(O)R^(a), S(O)NR^(a)R^(a),S(O)₂R^(a), or S(O)₂NR^(a)R^(a), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-14 membered heteroaryl)-C₁₋₄ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, are independentlyoptionally substituted with 1, 2, 3, or 4 R^(b) substituents; R^(a) isselected from hydrogen, cyano, C₁₋₆alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, or (4-10membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are independentlyoptionally substituted with 1, 2, 3, 4, or 5 R^(d) substituents; R^(b)is selected from halo, hydroxy, cyano, amino, nitro, C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, NHOR^(c), OR^(c), SR^(c), C(O)R^(c),C(O)NR^(c)R^(c), C(O)OR^(c), OC(O)R^(c), OC(O)NR^(c)R^(c),C(═NR^(c))NR^(c)R^(c), NR^(c)C(═NR^(c))NR^(c)R^(c), NHR^(c),NR^(c)R^(c), NR^(c)C(O)R^(c), NR^(c)C(O)OR^(c), NR^(c)(O)NR^(c)R^(c),NR^(c)S(O)R^(c), NR^(c)S(O)₂R^(c), NR^(c)S(O)₂NR^(c)R^(c), S(O)R^(c),S(O)NR^(c)R^(c), S(O)₂R^(c) or S(O)₂NR^(c)R^(c); wherein the C₁₋₄ alkyl,C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- are optionally substituted with 1, 2, or 3R^(d) substituents; R^(d) is selected from cyano, amino, C₁₋₆ alkyl,C₁₋₆ haloalkyl, halo, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, NHOR^(e), OR^(e), SR^(e),C(O)R^(e), C(O)NR^(e)R^(e), C(O)OR^(e), OC(O)R^(e), OC(O)NR^(e)R^(e),NHR^(e), NR^(e)R^(e), NR^(e)C(O)R^(e), NR^(e)C(O)NR^(e)R^(e),NR^(e)C(O)OR^(e), C(═NR^(e))NR^(e)R^(e), NR^(e)C(═NR^(e))NR^(e)R^(e),NR^(e)C(═NOH)NR^(e)R^(e), NR^(e)C(═NCN)NR^(e)R^(e), S(O)R^(e),S(O)NR^(e)R^(e), S(O)₂R^(e), NR^(e)S(O)₂R^(e), NR^(e)S(O)₂NR^(e)R^(e),or S(O)₂NR^(e)R^(e), wherein the C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- are optionally substituted with 1, 2, or 3R^(f) substituents; R^(c) is selected from hydrogen, C₁₋₆ alkyl, C₁₋₄haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, or (4-10 membered heterocycloalkyl)-C₁₋₄alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- are optionally substituted with 1, 2, 3,4, or 5 R^(f) substituent;R^(f) is selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, halogen, CN, NHOR^(g), OR^(g), SR^(g),C(O)R^(g), C(O)NR^(g)R^(g), C(O)OR^(g), OC(O)R^(g), OC(O)NR^(g)R^(g),NHR^(g), NR^(g)R^(g), NR^(g)C(O)R^(g), NR^(g)C(O)NR^(g)R^(g),NR^(g)C(O)OR^(g), C(═NR^(g))NR^(g)R^(g), NR^(g)C(═NR^(g))NR^(g)R^(g),S(O)R^(g), S(O)NR^(g)R^(g), S(O)₂R^(g), NR^(g)S(O)₂R^(g),NR^(g)S(O)₂NR^(g)R^(g), or S(O)₂NR^(g)R^(g); wherein the C₁₋₄ alkyl,C₁₋₄haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄alkyl- are optionally substituted with 1, 2, 3, 4, or 5 R^(n)substituents; R^(n) is selected from cyano, halo, C₁₋₄ alkyl, C₃₋₁₀cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 memberedheteroaryl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-6membered heteroaryl)-C₁₋₄ alkyl-, (4-7 membered heterocycloalkyl)-C₁₋₄alkyl-, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl,R^(o), NHOR^(o), OR^(o), SR^(o), C(O)R^(o), C(O)NR^(o)R^(o), C(O)OR^(o),OC(O)R^(o), OC(O)NR^(o)R^(o), NHR^(o), NR^(o)R^(o), NR^(o)C(O)R^(o),NR^(o)C(O)NR^(o)R^(o), NR^(o)C(O)OR^(o), C(═NR)NR^(o)R^(o),NR^(o)C(═NR^(o))NR^(o)R^(o), S(O)R^(o), S(O)NR^(o)R^(o), S(O)₂R^(o),NR^(o)S(O)₂R^(o), NR^(o)S(O)₂NR^(o)R^(o), or S(O)₂NR^(o)R^(o), whereinthe C₁₋₄ alkyl, C₃₋₁₀ cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀aryl, 5-6 membered heteroaryl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-6 membered heteroaryl)-C₁₋₄ alkyl-, (4-7membered heterocycloalkyl)-C₁₋₄ alkyl-, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl,C₂₋₆ alkynyl and C₁₋₄haloalkyl are optionally substituted with 1, 2 or 3R^(q) substituents; R^(g) is selected from hydrogen, C₁₋₆ alkyl, C₁₋₄haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, or (4-10 membered heterocycloalkyl)-C₁₋₄alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- are optionally substituted with 1, 2, or 3R^(p) substituents; R^(p) is selected from halo, cyano, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, NHOR^(r), OR^(r), SR^(r), C(O)R^(r),C(O)NR^(r)R^(r), C(O)OR^(r), OC(O)R^(r), OC(O)NR^(r)R^(r), NHR^(r),NR^(r)R^(r), NR^(r)C(O)R^(r), NR^(r)C(O)NR^(r)R^(r), NR^(r)C(O)OR^(r),C(═NR^(r))NR^(r)R^(r), NR^(r)C(═NR^(r))NR^(r)R^(r),NR^(r)C(═NOH)NR^(r)R^(r), NR^(r)C(═NCN)NR^(r)R^(r), S(O)R^(r),S(O)NR^(r)R^(r), S(O)₂R^(r), NR^(r)S(O)₂R^(r), NR^(r)S(O)₂NR^(r)R^(r) orS(O)₂NR^(r)R^(r), wherein the C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-are optionally substituted with 1, 2 or 3 R^(q) substituents; R^(e),R^(i), R^(k), R^(o) and R^(r) are independently selected from hydrogen,C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5 or 6-membered heteroaryl, 4-6membered heterocycloalkyl, C₁₋₄ haloalkyl, C₂₋₄ alkenyl, or C₂₋₄alkynyl, wherein the C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5 or6-membered heteroaryl, 4-6 membered heterocycloalkyl, C₂₋₄ alkenyl, andC₂₋₄ alkynyl are optionally substituted with 1, 2 or 3 R^(q)substituents; R^(q) is selected from hydroxy, cyano, amino, halo, COOH,C₁₋₆ haloalkyl, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylthio, C₅₋₆ aryl, 5-6membered heteroaryl, 4-6 membered heterocycloalkyl, C₃₋₆ cycloalkyl,NHR⁸, NR⁸R⁸, and C₁₋₄ haloalkoxy, wherein the C₁₋₆ alkyl, C₅₋₆ aryl,C₃₋₆ cycloalkyl, 4-6 membered heterocycloalkyl, and 5-6 memberedheteroaryl are optionally substituted with halo, hydroxy, cyano, COOH,amino, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₅₋₆aryl, C₃₋₁₀ cycloalkyl, 5-6 membered heteroaryl and 4-6 memberedheterocycloalkyl; R⁸ is C₁₋₆ alkyl; Ring B is selected from C₅₋₁₀ aryl,C₃₋₆ cycloalkyl, 5-10 membered monocyclic or bicyclic saturated orunsaturated heterocyclic ring with 1-3 heteroatoms selected from N, S orO.

In an embodiment of the present disclosure, there is provided a compoundof Formula II, their polymorphs, stereoisomers, tautomers, prodrugs,solvates, and pharmaceutically acceptable salts thereof, wherein X₁ isselected from —CH₂O—, —OCH₂—, —C(O)NH— or —NHC(O)—; R₄ is selected fromhydrogen, hydroxyl, C₁₋₆ alkyl, amino, —C(O)OR_(a1), C(O)NR_(b1)R_(c1),C₅₋₆ aryl, or C₁₋₆ heteroaryl, wherein C₁₋₆ alkyl is optionallysubstituted with one or more of the groups selected from the groupconsisting of hydrogen, hydroxyl, amino, —C(O)OR_(a1),C(O)NR_(b1)R_(c1), C₅₋₆ aryl, and C₁₋₆ heteroaryl; R_(a1), R_(b1), andR_(c1) are independently selected from hydrogen or C₁₋₆ alkyl; R₅ isselected from C₁₋₄ alkyl, cyano, or C₁₋₄ haloalkyl; R₃ is independentlyselected from hydrogen, halo, C(O)OR^(a), C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₆₋₁₀ aryl, or C₃₋₁₀cycloalkyl; R₁, R₂, R₆, and R₇ are independently selected from hydrogen,halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄alkyl-, (5-14 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a), SR^(a), NHOR^(a),C(O)R^(a), C(O)NR^(a)R^(a), C(O)OR^(a), OC(O)R^(a), OC(O)NR^(a)R^(a),NHR^(a), NR^(a)R^(a), NR^(a)C(O)R^(a), NR^(a)C(O)OR^(a),NR^(a)C(O)NR^(a)R^(a), C(═NR^(a))R^(a), C(═NR^(a))NR^(a)R^(a),NR^(a)C(═NR^(a))NR^(a)R^(a), NR^(a)S(O)R^(a), NR^(a)S(O)₂R^(a),NR^(a)S(O)₂NR^(a)R^(a), S(O)R^(a), S(O)NR^(a)R^(a), S(O)₂R^(a), orS(O)₂NR^(a)R^(a), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, are independently optionally substitutedwith 1, 2, 3, or 4 R^(b) substituents; R^(a) is selected from hydrogen,cyano, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, or (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10membered heterocycloalkyl)-C₁₋₄ alkyl- are independently optionallysubstituted with 1, 2, 3, 4, or 5 R^(d) substituents; R^(b) is selectedfrom halo, hydroxy, cyano, amino, nitro, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-,NHOR^(c), OR^(c), SR^(c), C(O)R^(c), C(O)NR^(c)R^(c), C(O)OR^(c),OC(O)R^(c), OC(O)NR^(c)R^(c), C(═NR^(c))NR^(c)R^(c),NR^(c)C(═NR^(c))NR^(c)R^(c), NHR^(c), NR^(c)R^(c), NR^(c)C(O)R^(c),NR^(c)C(O)OR^(c), NR^(c)(O)NR^(c)R^(c), NR^(c)S(O)R^(c),NR^(c)S(O)₂R^(c), NR^(c)S(O)₂NR^(c)R^(c), S(O)R^(c), S(O)NR^(c)R^(c),S(O)₂R^(c) or S(O)₂NR^(c)R^(c); wherein the C₁₋₄ alkyl, C₂₋₄ alkenyl,C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-are optionally substituted with 1, 2, or 3 R^(d) substituents; R^(d) isselected from cyano, amino, C₁₋₆ alkyl, C₁₋₆haloalkyl, halo, C₆₋₁₀ aryl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, NHOR^(e), OR^(e), SR^(e), C(O)R^(e),C(O)NR^(e)R^(e), C(O)OR^(e), OC(O)R^(e), OC(O)NR^(e)R^(e), NHR^(e),NR^(e)R^(e), NR^(e)C(O)R^(e), NR^(e)C(O)NR^(e)R^(e), NR^(e)C(O)OR^(e),C(═NR^(e))NR^(e)R^(e), NR^(e)C(═NR^(e))NR^(e)R^(e),NR^(e)C(═NOH)NR^(e)R^(e), NR^(e)C(═NCN)NR^(e)R^(e), S(O)R^(e),S(O)NR^(e)R^(e), S(O)₂R^(e), NR^(e)S(O)₂R^(e), NR^(e)S(O)₂NR^(e)R^(e),or S(O)₂NR^(e)R^(e), wherein the C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- are optionally substituted with 1, 2, or 3R^(f) substituents; R^(c) is selected from hydrogen, C₁₋₆ alkyl, C₁₋₄haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, or (4-10 membered heterocycloalkyl)-C₁₋₄alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- are optionally substituted with 1, 2, 3,4, or 5 R^(f) substituent;

R^(f) is selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, halogen, CN, NHOR^(g), OR^(g), SR^(g),C(O)R^(g), C(O)NR^(g)R^(g), C(O)OR^(g), OC(O)R^(g), OC(O)NR^(g)R^(g),NHR^(g), NR^(g)R^(g), NR^(g)C(O)R^(g), NR^(g)C(O)NR^(g)R^(g),NR^(g)C(O)OR^(g), C(═NR^(g))NR^(g)R^(g), NR^(g)C(═NR^(g))NR^(g)R^(g),S(O)R^(g), S(O)NR^(g)R^(g), S(O)₂R^(g), NR^(g)S(O)₂R^(g),NR^(g)S(O)₂NR^(g)R^(g), or S(O)₂NR^(g)R^(g); wherein the C₁₋₄ alkyl,C₁₋₄haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄alkyl- are optionally substituted with 1, 2, 3, 4, or 5 R^(n)substituents;R^(n) is selected from cyano, halo, C₁_₄ alkyl, C₃₋₁₀ cycloalkyl, 4-7membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-6 memberedheteroaryl)-C₁₋₄ alkyl-, (4-7 membered heterocycloalkyl)-C₁₋₄ alkyl-,C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl, R^(o),NHOR^(o), OR^(o), SR^(o), C(O)R^(o), C(O)NR^(o)R^(o), C(O)OR^(o),OC(O)R^(o), OC(O)NR^(o)R^(o), NHR^(o), NR^(o)R^(o), NR^(o)C(O)R^(o),NR^(o)C(O)NR^(o)R^(o), NR^(o)C(O)OR^(o), C(═NR)NR^(o)R^(o),NR^(o)C(═NR^(o))NR^(o)R^(o), S(O)R^(o), S(O)NR^(o)R^(o), S(O)₂R^(o),NR^(o)S(O)₂R^(o), NR^(o)S(O)₂NR^(o)R^(o), or S(O)₂NR^(o)R^(o), whereinthe C₁₋₄ alkyl, C₃₋₁₀ cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀aryl, 5-6 membered heteroaryl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-6 membered heteroaryl)-C₁₋₄ alkyl-, (4-7membered heterocycloalkyl)-C₁₋₄ alkyl-, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl,C₂₋₆ alkynyl and C₁₋₄haloalkyl are optionally substituted with 1, 2 or 3R^(q) substituents; R^(g) is selected from hydrogen, C₁₋₆ alkyl,C₁₋₄haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, or (4-10 membered heterocycloalkyl)-C₁₋₄alkyl-, wherein the C₁-6 alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- are optionally substituted with 1, 2, or 3R^(p) substituents; R^(p) is selected from halo, cyano, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, NHOR^(r), OR^(r), SR^(r), C(O)R^(r),C(O)NR^(r)R^(r), C(O)OR^(r), OC(O)R^(r), OC(O)NR^(r)R^(r), NHR^(r),NR^(r)R^(r), NR^(r)C(O)R^(r), NR^(r)C(O)NR^(r)R^(r), NR^(r)C(O)OR^(r),C(═NR)NR^(r), NR^(r)C(═NR^(r))NR^(r)R^(r), NR^(r)C(═NOH)NR^(r)R^(r),NR^(r)C(═NCN)NR^(r)R^(r), S(O)R^(r), S(O)NR^(r)R^(r), S(O)₂R^(r),NR^(r)S(O)₂R^(r), NR^(r)S(O)₂NR^(r)R^(r) or S(O)₂NR^(r)R^(r), whereinthe C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- are optionally substituted with 1, 2 or 3R^(q) substituents; R^(e), R^(i), R^(k), R^(o) and R^(r) areindependently selected from hydrogen, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀aryl, 5 or 6-membered heteroaryl, 4-6 membered heterocycloalkyl,C₁₋₄haloalkyl, C₂₋₄ alkenyl, or C₂₋₄ alkynyl, wherein the C₁₋₄ alkyl,C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5 or 6-membered heteroaryl, 4-6 memberedheterocycloalkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl are optionallysubstituted with 1, 2 or 3 R^(q) substituents; R^(q) is selected fromhydroxy, cyano, amino, halo, COOH, C₁₋₆ haloalkyl, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ alkylthio, C₅₋₆ aryl, 5-6 membered heteroaryl, 4-6 memberedheterocycloalkyl, C₃₋₆ cycloalkyl, NHR⁸, NR⁸R⁸, and C₁₋₄ haloalkoxy,wherein the C₁₋₆ alkyl, C₅₋₆ aryl, C₃₋₆ cycloalkyl, 4-6 memberedheterocycloalkyl, and 5-6 membered heteroaryl are optionally substitutedwith halo, hydroxy, cyano, COOH, amino, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄haloalkyl, C₁₋₄ haloalkoxy, C₅₋₆ aryl, C₃₋₁₀ cycloalkyl, 5-6 memberedheteroaryl and 4-6 membered heterocycloalkyl; R⁸ is C₁₋₆ alkyl; Ring Bis selected from C₅₋₁₀ aryl, C₃₋₆ cycloalkyl, 5-10 membered monocyclicor bicyclic saturated or unsaturated heterocyclic ring with 1-3heteroatoms selected from N, S or O.

In an embodiment of the present disclosure, there is provided a compoundof Formula III

their polymorphs, stereoisomers, tautomers, prodrugs, solvates, andpharmaceutically acceptable salts thereof, wherein X₁ is selected from—CH₂O—, —OCH₂—, —C(O)NH— or —NHC(O)—; R₄ is selected from hydrogen,hydroxyl, C₁₋₆ alkyl, amino, —C(O)OR_(a1), C(O)NR_(b1)R_(c1), C₅₋₆ aryl,or C₁₋₆ heteroaryl; wherein C₁₋₆ alkyl is optionally substituted withone or more of the groups selected from the group consisting ofhydrogen, hydroxyl, amino, —C(O)OR_(a1), C(O)NR_(b1)R_(c1), C₅₋₆ aryl,and C₁₋₆ heteroaryl; R_(a1), R_(b1), and R_(c1) are independentlyselected from hydrogen or C₁₋₆ alkyl; R₅ is selected from C₁₋₄ alkyl,cyano, or C₁₋₄ haloalkyl; R₁, R₂, R₃, R₆, and R₇ are independentlyselected from hydrogen, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-14 membered heteroaryl)-C₁₋₄alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a),SR^(a), NHOR^(a), C(O)R^(a), C(O)NR^(a)R^(a), C(O)OR^(a), OC(O)R^(a),OC(O)NR^(a)R^(a), NHR^(a), NR^(a)R^(a), NR^(a)C(O)R^(a),NR^(a)C(O)OR^(a), NR^(a)C(O)NR^(a)R^(a), C(═NR^(a))R^(a),C(═NR^(a))NR^(a)R^(a), NR^(a)C(═NR^(a))NR^(a)R^(a), NR^(a)S(O)R^(a),NR^(a)S(O)₂R^(a), NR^(a)S(O)₂NR^(a)R^(a), S(O)R^(a), S(O)NR^(a)R^(a),S(O)₂R^(a), or S(O)₂NR^(a)R^(a), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-14 membered heteroaryl)-C₁₋₄ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, are independentlyoptionally substituted with 1, 2, 3, or 4 R^(b) substituents; R^(a) isselected from hydrogen, cyano, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, or (4-10membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are independentlyoptionally substituted with 1, 2, 3, 4, or 5 R^(d) substituents; R^(b)is selected from halo, hydroxy, cyano, amino, nitro, C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, NHOR^(c), OR^(c), SR^(c), C(O)R^(c),C(O)NR^(c)R^(c), C(O)OR^(c), OC(O)R^(c), OC(O)NR^(c)R^(c),C(═NR^(c))NR^(c)R^(c), NR^(c)C(═NR^(c))NR^(c)R^(c), NHR^(c),NR^(c)R^(c), NR^(c)C(O)R^(c), NR^(c)C(O)OR^(c), NR^(c)C(O)NR^(c)R^(c),NR^(c)S(O)R^(c), NR^(c)S(O)₂R^(c), NR^(c)S(O)₂NR^(c)R^(c), S(O)R^(c),S(O)NR^(c)R^(c), S(O)₂R^(c) or S(O)₂NR^(c)R^(c); wherein the C₁₋₄ alkyl,C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- are optionally substituted with 1, 2, or 3R^(d) substituents; R^(d) is selected from cyano, amino, C₁₋₆ alkyl,C₁₋₆haloalkyl, halo, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, NHOR^(e), OR^(e), SR^(e),C(O)R^(e), C(O)NR^(e)R^(e), C(O)OR^(e), OC(O)R^(e), OC(O)NR^(e)R^(e),NHR^(e), NR^(e)R^(e), NR^(e)C(O)R^(e), NR^(e)C(O)NR^(e)R^(e),NR^(e)C(O)OR^(e), C(═NR^(e))NR^(e)R^(e), NR^(e)C(═NR^(e))NR^(e)R^(e),NR^(e)C(═NOH)NR^(e)R^(e), NR^(e)C(═NCN)NR^(e)R^(e), S(O)R^(e),S(O)NR^(e)R^(e), S(O)₂R^(e), NR^(e)S(O)₂R^(e), NR^(e)S(O)₂NR^(e)R^(e),or S(O)₂NR^(e)R^(e), wherein the C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- are optionally substituted with 1, 2, or 3R^(f) substituents; R^(c) is selected from hydrogen, C₁₋₆ alkyl, C₁₋₄haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, or (4-10 membered heterocycloalkyl)-C₁₋₄alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- are optionally substituted with 1, 2, 3,4, or 5 R^(f) substituent; R^(f) is selected from C₁₋₄ alkyl, C₁₋₄haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-,halogen, CN, NHOR^(g), OR^(g), SR^(g), C(O)R^(g), C(O)NR^(g)R^(g),C(O)OR^(g), OC(O)R^(g), OC(O)NR^(g)R^(g), NHR^(g), NR^(g)R^(g),NR^(g)C(O)R^(g), NR^(g)C(O)NR^(g)R^(g), NR^(g)C(O)OR^(g),C(═NR^(g))NR^(g)R^(g), NR^(g)C(═NR^(g))NR^(g)R^(g), S(O)R^(g),S(O)NR^(g)R^(g), S(O)₂R^(g), NR^(g)S(O)₂R^(g), NR^(g)S(O)₂NR^(g)R^(g),or S(O)₂NR^(g)R^(g); wherein the C₁₋₄ alkyl, C₁₋₄haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are optionallysubstituted with 1, 2, 3, 4, or 5 R^(n) substituents; R^(n) is selectedfrom cyano, halo, C₁₋₄ alkyl, C₃₋₁₀ cycloalkyl, 4-7 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-6 membered heteroaryl)-C₁₋₄alkyl-, (4-7 membered heterocycloalkyl)-C₁₋₄ alkyl-, C₁₋₆ haloalkoxy,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl, R^(o), NHOR^(o), OR^(o),SR^(o), C(O)R^(o), C(O)NR^(o)R^(o), C(O)OR^(o), OC(O)R^(o),OC(O)NR^(o)R^(o), NHR^(o), NR^(o)R^(o), NR^(o)C(O)R^(o),NR^(o)C(O)NR^(o)R^(o), NR^(o)C(O)OR^(o), C(═NR)NR^(o)R^(o),NR^(o)C(═NR^(o))NR^(o)R^(o), S(O)R^(o), S(O)NR^(o)R^(o), S(O)₂R^(o),NR^(o)S(O)₂R^(o), NR^(o)S(O)₂NR^(o)R^(o), or S(O)₂NR^(o)R^(o), whereinthe C₁₋₄ alkyl, C₃₋₁₀ cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀aryl, 5-6 membered heteroaryl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-6 membered heteroaryl)-C₁₋₄ alkyl-, (4-7membered heterocycloalkyl)-C₁₋₄ alkyl-, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl,C₂₋₆ alkynyl and C₁₋₄ haloalkyl are optionally substituted with 1, 2 or3 R^(q) substituents; R^(g) is selected from hydrogen, C₁₋₆ alkyl, C₁₋₄haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, or (4-10 membered heterocycloalkyl)-C₁₋₄alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- are optionally substituted with 1, 2, or 3R^(p) substituents; R^(p) is selected from halo, cyano, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, NHOR^(r), OR^(r), SR^(r), C(O)R^(r),C(O)NR^(r)R^(r), C(O)OR^(r), OC(O)R^(r), OC(O)NR^(r)R^(r), NHR^(r),NR^(r)R^(r), NR^(r)C(O)R^(r), NR^(r)C(O)NR^(r)R^(r), NR^(r)C(O)OR^(r),C(═NR^(r))NR^(r)R^(r), NR^(r)C(═NR^(r))NR^(r)R^(r),NR^(r)C(═NOH)NR^(r)R^(r), NR^(r)C(═NCN)NR^(r)R^(r), S(O)R^(r),S(O)NR^(r)R^(r), S(O)₂R^(r), NR^(r)S(O)₂R^(r), NR^(r)S(O)₂NR^(r)R^(r) orS(O)₂NR^(r)R^(r), wherein the C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆haloalkoxy,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are optionally substitutedwith 1, 2 or 3 R^(q) substituents; R^(e), R^(i), R^(k), R^(o) and R^(r)are independently selected from hydrogen, C₁₋₄ alkyl, C₃₋₆ cycloalkyl,C₆₋₁₀ aryl, 5 or 6-membered heteroaryl, 4-6 membered heterocycloalkyl,C₁₋₄ haloalkyl, C₂₋₄ alkenyl, or C₂₋₄ alkynyl, wherein the C₁₋₄ alkyl,C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5 or 6-membered heteroaryl, 4-6 memberedheterocycloalkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl are optionallysubstituted with 1, 2 or 3 R^(q) substituents; R^(q) is selected fromhydroxy, cyano, amino, halo, COOH, C₁₋₆ haloalkyl, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ alkylthio, C₅₋₆ aryl, 5-6 membered heteroaryl, 4-6 memberedheterocycloalkyl, C₃₋₆ cycloalkyl, NHR⁸, NR⁸R⁸, and C₁₋₄ haloalkoxy,wherein the C₁₋₆ alkyl, C₅₋₆ aryl, C₃₋₆ cycloalkyl, 4-6 memberedheterocycloalkyl, and 5-6 membered heteroaryl are optionally substitutedwith halo, hydroxy, cyano, COOH, amino, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄haloalkyl, C₁₋₄ haloalkoxy, C₅₋₆ aryl, C₃₋₁₀ cycloalkyl, 5-6 memberedheteroaryl and 4-6 membered heterocycloalkyl; R⁸ is C₁₋₆ alkyl.

In an embodiment of the present disclosure, there is provided a compoundof Formula III, their polymorphs, stereoisomers, tautomers, prodrugs,solvates, and pharmaceutically acceptable salts thereof, wherein X₁ isselected from —CH₂O—, —OCH₂—, or —C(O)NH—; R₄ is selected from hydrogen,hydroxyl, C₁₋₆ alkyl, amino, —C(O)OR_(a1), C(O)NR_(b1)R_(c1), C₅₋₆ aryl,or C₁₋₆ heteroaryl; wherein C₁₋₆ alkyl is optionally substituted withone or more of the groups selected from the group consisting ofhydrogen, hydroxyl, amino, —C(O)OR_(a1), C(O)NR_(b1)R_(c1), C₅₋₆ aryl,and C₁₋₆ heteroaryl; R_(a1), R_(b1), and R_(c1) are independentlyselected from hydrogen or C₁₋₆ alkyl; R₅ is selected from C₁₋₄ alkyl,cyano, or C₁₋₄ haloalkyl; R₃ is independently selected from hydrogen,halo, C(O)OR^(a), C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, C₆₋₁₀ aryl, or C₃₋₁₀ cycloalkyl; R₁, R₂, R₆,and R₇ are independently selected from hydrogen, halo, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a), SR^(a), NHOR^(a),C(O)R^(a), C(O)NR^(a)R^(a), C(O)OR^(a), OC(O)R^(a), OC(O)NR^(a)R^(a),NHR^(a), NR^(a)R^(a), NR^(a)C(O)R^(a), NR^(a)C(O)OR^(a),NR^(a)C(O)NR^(a)R^(a), C(═NR^(a))R^(a), C(═NR^(a))NR^(a)R^(a),NR^(a)C(═NR^(a))NR^(a)R^(a), NR^(a)S(O)R^(a), NR^(a)S(O)₂R^(a),NR^(a)S(O)₂NR^(a)R^(a), S(O)R^(a), S(O)NR^(a)R^(a), S(O)₂R^(a), orS(O)₂NR^(a)R^(a), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, are independently optionally substitutedwith 1, 2, 3, or 4 R^(b) substituents; R^(a) is selected from hydrogen,cyano, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, or (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10membered heterocycloalkyl)-C₁₋₄ alkyl- are independently optionallysubstituted with 1, 2, 3, 4, or 5 R^(d) substituents; R^(b) is selectedfrom halo, hydroxy, cyano, amino, nitro, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-,NHOR^(c), OR^(c), SR^(c), C(O)R^(c), C(O)NR^(c)R^(c), C(O)OR^(c),OC(O)R^(c), OC(O)NR^(c)R^(c), C(═NR^(c))NR^(c)R^(c),NR^(c)C(═NR^(c))NR^(c)R^(c), NHR^(c), NR^(c)R^(c), NR^(c)C(O)R^(c),NR^(c)C(O)OR^(c), NR^(c)C(O)NR^(c)R^(c), NR^(c)S(O)R^(c),NR^(c)S(O)₂R^(c), NR^(c)S(O)₂NR^(c)R^(c), S(O)R^(c), S(O)NR^(c)R^(c),S(O)₂R^(c) or S(O)₂NR^(c)R^(c); wherein the C₁₋₄ alkyl, C₂₋₄ alkenyl,C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-are optionally substituted with 1, 2, or 3 R^(d) substituents; R^(d) isselected from cyano, amino, C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo, C₆₋₁₀aryl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, NHOR^(e), OR^(e), SR^(e), C(O)R^(e),C(O)NR^(e)R^(e), C(O)OR^(e), OC(O)R^(e), OC(O)NR^(e)R^(e), NHR^(e),NR^(e)R^(e), NR^(e)C(O)R^(e), NR^(e)C(O)NR^(e)R^(e), NR^(e)C(O)OR^(e),C(═NR^(e))NR^(e)R^(e), NR^(e)C(═NR^(e))NR^(e)R^(e),NR^(e)C(═NOH)NR^(e)R^(e), NR^(e)C(═NCN)NR^(e)R^(e), S(O)R^(e),S(O)NR^(e)R^(e), S(O)₂R^(e), NR^(e)S(O)₂R^(e), NR^(e)S(O)₂NR^(e)R^(e),or S(O)₂NR^(e)R^(e), wherein the C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- are optionally substituted with 1, 2, or 3R^(f) substituents; R^(c) is selected from hydrogen, C₁₋₆ alkyl, C₁₋₄haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, or (4-10 membered heterocycloalkyl)-C₁₋₄alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- are optionally substituted with 1, 2, 3,4, or 5 R^(f) substituent; R^(f) is selected from C₁₋₄ alkyl, C₁₋₄haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-,halogen, CN, NHOR^(g), OR^(g), SR^(g), C(O)R^(g), C(O)NR^(g)R^(g),C(O)OR^(g), OC(O)R^(g), OC(O)NR^(g)R^(g), NHR^(g), NR^(g)R^(g),NR^(g)C(O)R^(g), NR^(g)C(O)NR^(g)R^(g), NR^(g)C(O)OR^(g),C(═NR^(g))NR^(g)R^(g), NR^(g)C(═NR^(g))NR^(g)R^(g), S(O)R^(g),S(O)NR^(g)R^(g), S(O)₂R^(g), NR^(g)S(O)₂R^(g), NR^(g)S(O)₂NR^(g)R^(g),or S(O)₂NR^(g)R^(g); wherein the C₁₋₄ alkyl, C₁₋₄haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are optionallysubstituted with 1, 2, 3, 4, or 5 R^(n) substituents; R^(n) is selectedfrom cyano, halo, C₁₋₄ alkyl, C₃₋₁₀ cycloalkyl, 4-7 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-6 membered heteroaryl)-C₁₋₄alkyl-, (4-7 membered heterocycloalkyl)-C₁₋₄ alkyl-, C₁₋₆ haloalkoxy,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl, R^(o), NHOR^(o), OR^(o),SR^(o), C(O)R^(o), C(O)NR^(o)R^(o), C(O)OR^(o), OC(O)R^(o),OC(O)NR^(o)R^(o), NHR^(o), NR^(o)R^(o), NR^(o)C(O)R^(o),NR^(o)C(O)NR^(o)R^(o), NR^(o)C(O)OR^(o), C(═NR)NR^(o)R^(o),NR^(o)C(═NR^(o))NR^(o)R^(o), S(O)R^(o), S(O)NR^(o)R^(o), S(O)₂R^(o),NR^(o)S(O)₂R^(o), NR^(o)S(O)₂NR^(o)R^(o), or S(O)₂NR^(o)R^(o), whereinthe C₁₋₄ alkyl, C₃₋₁₀ cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀aryl, 5-6 membered heteroaryl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-6 membered heteroaryl)-C₁₋₄ alkyl-, (4-7membered heterocycloalkyl)-C₁₋₄ alkyl-, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl,C₂₋₆ alkynyl and C₁₋₄ haloalkyl are optionally substituted with 1, 2 or3 R^(q) substituents; R^(g) is selected from hydrogen, C₁₋₆ alkyl, C₁₋₄haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, or (4-10 membered heterocycloalkyl)-C₁₋₄alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- are optionally substituted with 1, 2, or 3R^(p) substituents; R^(p) is selected from halo, cyano, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, NHOR^(r), OR^(r), SR^(r), C(O)R^(r),C(O)NR^(r)R^(r), C(O)OR^(r), OC(O)R^(r), OC(O)NR^(r)R^(r), NHR^(r),NR^(r)R^(r), NR^(r)C(O)R^(r), NR^(r)C(O)NR^(r)R^(r), NR^(r)C(O)OR^(r),C(═NR^(r))NR^(r)R^(r), NR^(r)C(═NR^(r))NR^(r)R^(r),NR^(r)C(═NOH)NR^(r)R^(r), NR^(r)C(═NCN)NR^(r)R^(r), S(O)R^(r),S(O)NR^(r)R^(r), S(O)₂R^(r), NR^(r)S(O)₂R^(r), NR^(r)S(O)₂NR^(r)R^(r) orS(O)₂NR^(r)R^(r), wherein the C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆haloalkoxy,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are optionally substitutedwith 1, 2 or 3 R^(q) substituents; R^(e), R^(i), R^(k), R^(o) and R^(r)are independently selected from hydrogen, C₁₋₄ alkyl, C₃₋₆ cycloalkyl,C₆₋₁₀ aryl, 5 or 6-membered heteroaryl, 4-6 membered heterocycloalkyl,C₁₋₄ haloalkyl, C₂₋₄ alkenyl, or C₂₋₄ alkynyl, wherein the C₁₋₄ alkyl,C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5 or 6-membered heteroaryl, 4-6 memberedheterocycloalkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl are optionallysubstituted with 1, 2 or 3 R^(q) substituents; R^(q) is selected fromhydroxy, cyano, amino, halo, COOH, C₁₋₆ haloalkyl, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ alkylthio, C₅₋₆ aryl, 5-6 membered heteroaryl, 4-6 memberedheterocycloalkyl, C₃₋₆ cycloalkyl, NHR⁸, NR⁸R⁸, and C₁₋₄ haloalkoxy,wherein the C₁₋₆ alkyl, C₅₋₆ aryl, C₃₋₆ cycloalkyl, 4-6 memberedheterocycloalkyl, and 5-6 membered heteroaryl are optionally substitutedwith halo, hydroxy, cyano, COOH, amino, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄haloalkyl, C₁₋₄ haloalkoxy, C₅₋₆ aryl, C₃₋₁₀ cycloalkyl, 5-6 memberedheteroaryl and 4-6 membered heterocycloalkyl; R⁸ is C₁₋₆ alkyl.

In an embodiment of the present disclosure, there is provided a compoundof Formula IV

their polymorphs, stereoisomers, tautomers, prodrugs, solvates, andpharmaceutically acceptable salts thereof, wherein R₅ is selected fromC₁₋₄ alkyl, cyano, or C₁₋₄ haloalkyl; R₁, R₂, R₃, R₆, and R₇ areindependently selected from hydrogen, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-14 memberedheteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-,CN, NO₂, OR^(a), SR^(a), NHOR^(a), C(O)R^(a), C(O)NR^(a)R^(a),C(O)OR^(a), OC(O)R^(a), OC(O)NR^(a)R^(a), NHR^(a), NR^(a)R^(a),NR^(a)C(O)R^(a), NR^(a)C(O)OR^(a), NR^(a)C(O)NR^(a)R^(a),C(═NR^(a))R^(a), C(═NR^(a))NR^(a)R^(a), NR^(a)C(═NR^(a))NR^(a)R^(a),NR^(a)S(O)R^(a), NR^(a)S(O)₂R^(a), NR^(a)S(O)₂NR^(a)R^(a), S(O)R^(a),S(O)NR^(a)R^(a), S(O)₂R^(a), or S(O)₂NR^(a)R^(a), wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄alkyl-, (5-14 membered heteroaryl)-C₁₋₄alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, areindependently optionally substituted with 1, 2, 3, or 4 R^(b)substituents; R^(a) is selected from hydrogen, cyano, C₁₋₆ alkyl, C₁₋₄haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, or (4-10 membered heterocycloalkyl)-C₁₋₄alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- are independently optionally substitutedwith 1, 2, 3, 4, or 5 R^(d) substituents; R^(b) is selected from halo,hydroxy, cyano, amino, nitro, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, NHOR^(c), OR^(c),SR^(c), C(O)R^(c), C(O)NR^(c)R^(c), C(O)OR^(c), OC(O)R^(c),OC(O)NR^(c)R^(c), C(═NR^(c))NR^(c)R^(c), NR^(c)C(═NR^(c))NR^(c)R^(c),NHR^(c), NR^(c)R^(c), NR^(c)C(O)R^(c), NR^(c)C(O)OR^(c),NR^(c)C(O)NR^(c)R^(c), NR^(c)S(O)R^(c), NR^(c)S(O)₂R^(c),NR^(c)S(O)₂NR^(c)R^(c), S(O)R^(c), S(O)NR^(c)R^(c), S(O)₂R^(c) orS(O)₂NR^(c)R^(c); wherein the C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are optionallysubstituted with 1, 2, or 3 R^(d) substituents;R^(d) is selected from cyano, amino, C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo,C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, NHOR^(e), OR^(e), SR^(e), C(O)R^(e),C(O)NR^(e)R^(e), C(O)OR^(e), OC(O)R^(e), OC(O)NR^(e)R^(e), NHR^(e),NR^(e)R^(e), NR^(e)C(O)R^(e), NR^(e)C(O)NR^(e)R^(e), NR^(e)C(O)OR^(e),C(═NR^(e))NR^(e)R^(e), NR^(e)C(═NR^(e))NR^(e)R^(e),NR^(e)C(═NOH)NR^(e)R^(e), NR^(e)C(═NCN)NR^(e)R^(e), S(O)R^(e),S(O)NR^(e)R^(e), S(O)₂R^(e), NR^(e)S(O)₂R^(e), NR^(e)S(O)₂NR^(e)R^(e),or S(O)₂NR^(e)R^(e), wherein the C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- are optionally substituted with 1, 2, or 3R^(f) substituents; R^(c) is selected from hydrogen, C₁₋₆ alkyl, C₁₋₄haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, or (4-10 membered heterocycloalkyl)-C₁₋₄alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- are optionally substituted with 1, 2, 3,4, or 5 R^(f) substituent; R^(f) is selected from C₁₋₄ alkyl,C₁₋₄haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-,halogen, CN, NHOR^(g), OR^(g), SR^(g), C(O)R^(g), C(O)NR^(g)R^(g),C(O)OR^(g), OC(O)R^(g), OC(O)NR^(g)R^(g), NHR^(g), NR^(g)R^(g),NR^(g)C(O)R^(g), NR^(g)C(O)NR^(g)R^(g), NR^(g)C(O)OR^(g),C(═NR^(g))NR^(g)R^(g), NR^(g)C(═NR^(g))NR^(g)R^(g), S(O)R^(g),S(O)NR^(g)R^(g), S(O)₂R^(g), NR^(g)S(O)₂R^(g), NR^(g)S(O)₂NR^(g)R^(g),or S(O)₂NR^(g)R^(g); wherein the C₁₋₄ alkyl, C₁₋₄haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are optionallysubstituted with 1, 2, 3, 4, or 5 R^(n) substituents; R^(n) is selectedfrom cyano, halo, C₁₋₄ alkyl, C₃₋₁₀ cycloalkyl, 4-7 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-6 membered heteroaryl)-C₁₋₄alkyl-, (4-7 membered heterocycloalkyl)-C₁₋₄ alkyl-, C₁₋₆ haloalkoxy,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl, R^(o), NHOR^(o), OR^(o),SR^(o), C(O)R^(o), C(O)NR^(o)R^(o), C(O)OR^(o), OC(O)R^(o),OC(O)NR^(o)R^(o), NHR^(o), NR^(o)R^(o), NR^(o)C(O)R^(o),NR^(o)C(O)NR^(o)R^(o), NR^(o)C(O)OR^(o), C(═NR)NR^(o)R^(o),NR^(o)C(═NR^(o))NR^(o)R^(o), S(O)R^(o), S(O)NR^(o)R^(o), S(O)₂R^(o),NR^(o)S(O)₂R^(o), NR^(o)S(O)₂NR^(o)R^(o), or S(O)₂NR^(o)R^(o), whereinthe C₁₋₄ alkyl, C₃₋₁₀ cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀aryl, 5-6 membered heteroaryl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-6 membered heteroaryl)-C₁₋₄ alkyl-, (4-7membered heterocycloalkyl)-C₁₋₄ alkyl-, C₁₋₆haloalkoxy, C₂₋₆ alkenyl,C₂₋₆ alkynyl and C₁₋₄haloalkyl are optionally substituted with 1, 2 or 3R^(q) substituents; R^(g) is selected from hydrogen, C₁₋₆ alkyl, C₁₋₄haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, or (4-10 membered heterocycloalkyl)-C₁₋₄alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- are optionally substituted with 1, 2, or 3R^(p) substituents; R^(p) is selected from halo, cyano, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, NHOR^(r), SR^(r), C(O)R^(r),C(O)NR^(r)R^(r), C(O)OR^(r), OC(O)R^(r), OC(O)NR^(r)R^(r), NHR^(r),NR^(r)R^(r), NR^(r)C(O)R^(r), NR^(r)C(O)NR^(r)R^(r), NR^(r)C(O)OR^(r),C(═NR^(r))NR^(r)R^(r), NR^(r)C(═NR)NR^(r)R^(r),NR^(r)C(═NOH)NR^(r)R^(r), NR^(r)C(═NCN)NR^(r)R^(r), S(O)R^(r),S(O)NR^(r)R^(r), S(O)₂R^(r), NR^(r)S(O)₂R^(r), NR^(r)S(O)₂NR^(r)R^(r) orS(O)₂NR^(r)R^(r), wherein the C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-are optionally substituted with 1, 2 or 3 R^(q) substituents; R^(e),R^(i), R^(k), R^(o) and R^(r) are independently selected from hydrogen,C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5 or 6-membered heteroaryl, 4-6membered heterocycloalkyl, C₁₋₄ haloalkyl, C₂₋₄ alkenyl, or C₂₋₄alkynyl, wherein the C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5 or6-membered heteroaryl, 4-6 membered heterocycloalkyl, C₂₋₄ alkenyl, andC₂₋₄ alkynyl are optionally substituted with 1, 2 or 3 R^(q)substituents; R^(q) is selected from hydroxy, cyano, amino, halo, COOH,C₁₋₆ haloalkyl, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylthio, C₅₋₆ aryl, 5-6membered heteroaryl, 4-6 membered heterocycloalkyl, C₃₋₆ cycloalkyl,NHR⁸, NR⁸R⁸, and C₁₋₄ haloalkoxy, wherein the C₁₋₆ alkyl, C₅₋₆ aryl,C₃₋₆ cycloalkyl, 4-6 membered heterocycloalkyl, and 5-6 memberedheteroaryl are optionally substituted with halo, hydroxy, cyano, COOH,amino, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₅₋₆aryl, C₃₋₁₀ cycloalkyl, 5-6 membered heteroaryl and 4-6 memberedheterocycloalkyl; R⁸ is C₁₋₆ alkyl.

In an embodiment of the present disclosure, there is provided a compoundof Formula IV, their polymorphs, stereoisomers, tautomers, prodrugs,solvates, and pharmaceutically acceptable salts thereof, wherein R₅ isselected from C₁₋₄ alkyl, cyano, or C₁₋₄ haloalkyl; R₃ is independentlyselected from hydrogen, halo, C(O)OR^(a), C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₆₋₁₀ aryl, or C₃₋₁₀cycloalkyl; R₁, R₂, R₆, and R₇ are independently selected from hydrogen,halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄alkyl-, (5-14 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a), SR^(a), NHOR^(a),C(O)R^(a), C(O)NR^(a)R^(a), C(O)OR^(a), OC(O)R^(a), OC(O)NR^(a)R^(a),NHR^(a), NR^(a)R^(a), NR^(a)C(O)R^(a), NR^(a)C(O)OR^(a),NR^(a)C(O)NR^(a)R^(a), C(═NR^(a))R^(a), C(═NR^(a))NR^(a)R^(a),NR^(a)C(═NR^(a))NR^(a)R^(a), NR^(a)S(O)R^(a), NR^(a)S(O)₂R^(a),NR^(a)S(O)₂NR^(a)R^(a), S(O)R^(a), S(O)NR^(a)R^(a), S(O)₂R^(a), orS(O)₂NR^(a)R^(a), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, are independently optionally substitutedwith 1, 2, 3, or 4 R^(b) substituents; R^(a) is selected from hydrogen,cyano, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, or (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10membered heterocycloalkyl)-C₁₋₄ alkyl- are independently optionallysubstituted with 1, 2, 3, 4, or 5 R^(d) substituents; R^(b) is selectedfrom halo, hydroxy, cyano, amino, nitro, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-,NHOR^(c), OR^(c), SR^(c), C(O)R^(c), C(O)NR^(c)R^(c), C(O)OR^(c),OC(O)R^(c), OC(O)NR^(c)R^(c), C(═NR^(c))NR^(c)R^(c),NR^(c)C(═NR^(c))NR^(c)R^(c), NHR^(c), NR^(c)R^(c), NR^(c)C(O)R^(c),NR^(c)C(O)OR^(c), NR^(c)C(O)NR^(c)R^(c), NR^(c)S(O)R^(c),NR^(c)S(O)₂R^(c), NR^(c)S(O)₂NR^(c)R^(c), S(O)R^(c), S(O)NR^(c)R^(c),S(O)₂R^(c) or S(O)₂NR^(c)R^(c); wherein the C₁₋₄ alkyl, C₂₋₄ alkenyl,C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-are optionally substituted with 1, 2, or 3 R^(d) substituents; R^(d) isselected from cyano, amino, C₁₋₆ alkyl, C₁₋₆haloalkyl, halo, C₁₋₁₀ aryl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, NHOR^(e), OR^(e), SR^(e), C(O)R^(e),C(O)NR^(e)R^(e), C(O)OR^(e), OC(O)R^(e), OC(O)NR^(e)R^(e), NHR^(e),NR^(e)R^(e), NR^(e)C(O)R^(e), NR^(e)C(O)NR^(e)R^(e), NR^(e)C(O)OR^(e),C(═NR^(e))NR^(e)R^(e), NR^(e)C(═NR^(e))NR^(e)R^(e),NR^(e)C(═NOH)NR^(e)R^(e), NR^(e)C(═NCN)NR^(e)R^(e), S(O)R^(e),S(O)NR^(e)R^(e), S(O)₂R^(e), NR^(e)S(O)₂R^(e), NR^(e)S(O)₂NR^(e)R^(e),or S(O)₂NR^(e)R^(e), wherein the C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- are optionally substituted with 1, 2, or 3R^(f) substituents; R^(c) is selected from hydrogen, C₁₋₆ alkyl, C₁₋₄haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, or (4-10 membered heterocycloalkyl)-C₁₋₄alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- are optionally substituted with 1, 2, 3,4, or 5 R^(f) substituent; R^(f) is selected from C₁₋₄ alkyl, C₁₋₄haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-,halogen, CN, NHOR^(g), OR^(g), SR^(g), C(O)R^(g), C(O)NR^(g)R^(g),C(O)OR^(g), OC(O)R^(g), OC(O)NR^(g)R^(g), NHR^(g), NR^(g)R^(g),NR^(g)C(O)R^(g), NR^(g)C(O)NR^(g)R^(g), NR^(g)C(O)OR^(g),C(═NR^(g))NR^(g)R^(g), NR^(g)C(═NR^(g))NR^(g)R^(g), S(O)R^(g),S(O)NR^(g)R^(g), S(O)₂R^(g), NR^(g)S(O)₂R^(g), NR^(g)S(O)₂NR^(g)R^(g),or S(O)₂NR^(g)R^(g); wherein the C₁₋₄ alkyl, C₁₋₄haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are optionallysubstituted with 1, 2, 3, 4, or 5 R^(n) substituents; R^(n) is selectedfrom cyano, halo, C₁₋₄ alkyl, C₃₋₁₀ cycloalkyl, 4-7 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-6 membered heteroaryl)-C₁₋₄alkyl-, (4-7 membered heterocycloalkyl)-C₁₋₄ alkyl-, C₁₋₆ haloalkoxy,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl, R^(o), NHOR^(o), OR^(o),SR^(o), C(O)R^(o), C(O)NR^(o)R^(o), C(O)OR^(o), OC(O)R^(o),OC(O)NR^(o)R^(o), NHR^(o), NR^(o)R^(o), NR^(o)C(O)R^(o),NR^(o)C(O)NR^(o)R^(o), NR^(o)C(O)OR^(o), C(═NR)NR^(o)R^(o),NR^(o)C(═NR^(o))NR^(o)R^(o), S(O)R^(o), S(O)NR^(o)R^(o), S(O)₂R^(o),NR^(o)S(O)₂R^(o), NR^(o)S(O)₂NR^(o)R^(o), or S(O)₂NR^(o)R^(o), whereinthe C₁₋₄ alkyl, C₃₋₁₀ cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀aryl, 5-6 membered heteroaryl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-6 membered heteroaryl)-C₁₋₄ alkyl-, (4-7membered heterocycloalkyl)-C₁₋₄ alkyl-, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl,C₂₋₆ alkynyl and C₁₋₄haloalkyl are optionally substituted with 1, 2 or 3R^(q) substituents; R^(g) is selected from hydrogen, C₁₋₆ alkyl, C₁₋₄haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, or (4-10 membered heterocycloalkyl)-C₁₋₄alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- are optionally substituted with 1, 2, or 3R^(p) substituents; R^(p) is selected from halo, cyano, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, NHOR^(r), SR^(r), C(O)R^(r),C(O)NR^(r)R^(r), C(O)OR^(r), OC(O)R^(r), OC(O)NR^(r)R^(r), NHR^(r),NR^(r)R^(r), NR^(r)C(O)R^(r), NR^(r)C(O)NR^(r)R^(r), NR^(r)C(O)OR^(r),C(═NR^(r))NR^(r)R^(r), NR^(r)C(═NR^(r))NR^(r)R^(r),NR^(r)C(═NOH)NR^(r)R^(r), NR^(r)C(═NCN)NR^(r)R^(r), S(O)R^(r),S(O)NR^(r)R^(r), S(O)₂R^(r), NR^(r)S(O)₂R^(r), NR^(r)S(O)₂NR^(r)R^(r) orS(O)₂NR^(r)R^(r), wherein the C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-are optionally substituted with 1, 2 or 3 R^(q) substituents; R^(e),R^(i), R^(k), R^(o) and R are independently selected from hydrogen, C₁₋₄alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5 or 6-membered heteroaryl, 4-6membered heterocycloalkyl, C₁₋₄ haloalkyl, C₂₋₄ alkenyl, or C₂₋₄alkynyl, wherein the C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5 or6-membered heteroaryl, 4-6 membered heterocycloalkyl, C₂₋₄ alkenyl, andC₂₋₄ alkynyl are optionally substituted with 1, 2 or 3 R^(q)substituents; R^(q) is selected from hydroxy, cyano, amino, halo, COOH,C₁₋₆ haloalkyl, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylthio, C₅₋₆ aryl, 5-6membered heteroaryl, 4-6 membered heterocycloalkyl, C₃₋₆ cycloalkyl,NHR⁸, NR⁸R⁸, and C₁₋₄ haloalkoxy, wherein the C₁₋₆ alkyl, C₅₋₆ aryl,C₃₋₆ cycloalkyl, 4-6 membered heterocycloalkyl, and 5-6 memberedheteroaryl are optionally substituted with halo, hydroxy, cyano, COOH,amino, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₅₋₆aryl, C₃₋₁₀ cycloalkyl, 5-6 membered heteroaryl and 4-6 memberedheterocycloalkyl; R⁸ is C₁₋₆ alkyl.

In an embodiment of the present disclosure, there is provided A compoundof Formula V

their polymorphs, stereoisomers, tautomers, prodrugs, solvates, andpharmaceutically acceptable salts thereof, wherein R₅ is selected fromC₁₋₄ alkyl, cyano, or C₁₋₄ haloalkyl; R₄ is selected from hydrogen,hydroxyl, C₁₋₆ alkyl, amino, —C(O)OR_(a1), C(O)NR_(b1)R_(c1), C₅₋₆ aryl,or C₁₋₆ heteroaryl; wherein C₁₋₆ alkyl is optionally substituted withone or more of the groups selected from the group consisting ofhydrogen, hydroxyl, amino, —C(O)OR_(a1), C(O)NR_(b1)R_(c1), C₅₋₆ aryl,and C₁₋₆ heteroaryl; R_(a1), R_(b1), and R_(c1) are independentlyselected from hydrogen or C₁₋₆ alkyl; R₁, R₂, R₃, R₆, and R₇ areindependently selected from hydrogen, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-14 memberedheteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-,CN, NO₂, OR^(a), SR^(a), NHOR^(a), C(O)R^(a), C(O)NR^(a)R^(a),C(O)OR^(a), OC(O)R^(a), OC(O)NR^(a)R^(a), NHR^(a), NR^(a)R^(a),NR^(a)C(O)R^(a), NR^(a)C(O)OR^(a), NR^(a)C(O)NR^(a)R^(a),C(═NR^(a))R^(a), C(═NR^(a))NR^(a)R^(a), NR^(a)C(═NR^(a))NR^(a)R^(a),NR^(a)S(O)R^(a), NR^(a)S(O)₂R^(a), NR^(a)S(O)₂NR^(a)R^(a), S(O)R^(a),S(O)NR^(a)R^(a), S(O)₂R^(a), or S(O)₂NR^(a)R^(a), wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-14 membered heteroaryl)-C₁₋₄alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, areindependently optionally substituted with 1, 2, 3, or 4 R^(b)substituents; R^(a) is selected from hydrogen, cyano, C₁₋₆ alkyl, C₁₋₄haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, or (4-10 membered heterocycloalkyl)-C₁₋₄alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- are independently optionally substitutedwith 1, 2, 3, 4, or 5 R^(d) substituents; R^(b) is selected from halo,hydroxy, cyano, amino, nitro, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, NHOR^(c), OR^(c),SR^(c), C(O)R^(c), C(O)NR^(c)R^(c), C(O)OR^(c), OC(O)R^(c),OC(O)NR^(c)R^(c), C(═NR^(c))NR^(c)R^(c), NR^(c)C(═NR^(c))NR^(c)R^(c),NHR^(c), NR^(c)R^(c), NR^(c)C(O)R^(c), NR^(c)C(O)OR^(c),NR^(c)(O)NR^(c)R^(c), NR^(c)S(O)R^(c), NR^(c)S(O)₂R^(c),NR^(c)S(O)₂NR^(c)R^(c), S(O)R^(c), S(O)NR^(c)R^(c), S(O)₂R^(c) orS(O)₂NR^(c)R^(c); wherein the C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are optionallysubstituted with 1, 2, or 3 R^(d) substituents; R^(d) is selected fromcyano, amino, C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo, C₆₋₁₀ aryl, 5-10membered heteroaryl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-,NHOR^(e), OR^(e), SR^(e), C(O)R^(e), C(O)NR^(e)R^(e), C(O)OR^(e),OC(O)R^(e), OC(O)NR^(e)R^(e), NHR^(e), NR^(e)R^(e), NR^(e)C(O)R^(e),NR^(e)C(O)NR^(e)R^(e), NR^(e)C(O)OR^(e), C(═NR^(e))NR^(e)R^(e),NR^(e)C(═NR^(e))NR^(e)R^(e), NR^(e)C(═NOH)NR^(e)R^(e),NR^(e)C(═NCN)NR^(e)R^(e), S(O)R^(e), S(O)NR^(e)R^(e), S(O)₂R^(e),NR^(e)S(O)₂R^(e), NR^(e)S(O)₂NR^(e)R^(e), or S(O)₂NR^(e)R^(e), whereinthe C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are optionallysubstituted with 1, 2, or 3 R^(f) substituents; R^(c) is selected fromhydrogen, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, or (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10membered heterocycloalkyl)-C₁₋₄ alkyl- are optionally substituted with1, 2, 3, 4, or 5 R^(f) substituent; R^(f) is selected from C₁₋₄ alkyl,C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-,halogen, CN, NHOR^(g), OR^(g), SR^(g), C(O)R^(g), C(O)NR^(g)R^(g),C(O)OR^(g), OC(O)R^(g), OC(O)NR^(g)R^(g), NHR^(g), NR^(g)R^(g),NR^(g)C(O)R^(g), NR^(g)C(O)NR^(g)R^(g), NR^(g)C(O)OR^(g),C(═NR^(g))NR^(g)R^(g), NR^(g)C(═NR^(g))NR^(g)R^(g), S(O)R^(g),S(O)NR^(g)R^(g), S(O)₂R^(g), NR^(g)S(O)₂R^(g), NR^(g)S(O)₂NR^(g)R^(g),or S(O)₂NR^(g)R^(g); wherein the C₁₋₄ alkyl, C₁₋₄haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are optionallysubstituted with 1, 2, 3, 4, or 5 R^(n) substituents; R^(n) is selectedfrom cyano, halo, C₁₋₄ alkyl, C₃₋₁₀ cycloalkyl, 4-7 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-6 membered heteroaryl)-C₁₋₄alkyl-, (4-7 membered heterocycloalkyl)-C₁₋₄ alkyl-, C₁₋₆ haloalkoxy,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl, R^(o), NHOR^(o), OR^(o),SR^(o), C(O)R^(o), C(O)NR^(o)R^(o), C(O)OR^(o), OC(O)R^(o),OC(O)NR^(o)R^(o), NHR^(o), NR^(o)R^(o), NR^(o)C(O)R^(o),NR^(o)C(O)NR^(o)R^(o), NR^(o)C(O)OR^(o), C(═NR)NR^(o)R^(o),NR^(o)C(═NR^(o))NR^(o)R^(o), S(O)R^(o), S(O)NR^(o)R^(o), S(O)₂R^(o),NR^(o)S(O)₂R^(o), NR^(o)S(O)₂NR^(o)R^(o), or S(O)₂NR^(o)R^(o), whereinthe C₁₋₄ alkyl, C₃₋₁₀ cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀aryl, 5-6 membered heteroaryl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-6 membered heteroaryl)-C₁₋₄ alkyl-, (4-7membered heterocycloalkyl)-C₁₋₄ alkyl-, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl,C₂₋₆ alkynyl and C₁₋₄haloalkyl are optionally substituted with 1, 2 or 3R^(q) substituents; R^(g) is selected from hydrogen, C₁₋₆ alkyl, C₁₋₄haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, or (4-10 membered heterocycloalkyl)-C₁₋₄alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- are optionally substituted with 1, 2, or 3R^(p) substituents; R^(p) is selected from halo, cyano, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, NHOR^(r), OR^(r), SR^(r), C(O)R^(r),C(O)NR^(r)R^(r), C(O)OR^(r), OC(O)R^(r), OC(O)NR^(r)R^(r), NHR^(r),NR^(r)R^(r), NR^(r)C(O)R^(r), NR^(r)C(O)NR^(r)R^(r), NR^(r)C(O)OR^(r),C(═NR^(r))NR^(r)R^(r), NR^(r)C(═NR^(r))NR^(r)R^(r),NR^(r)C(═NOH)NR^(r)R^(r), NR^(r)C(═NCN)NR^(r)R^(r), S(O)R^(r),S(O)NR^(r)R^(r), S(O)₂R^(r), NR^(r)S(O)₂R^(r), NR^(r)S(O)₂NR^(r)R^(r) orS(O)₂NR^(r)R^(r), wherein the C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-are optionally substituted with 1, 2 or 3 R^(q) substituents; R^(e),R^(i), R^(k), R^(o) and R^(r) are independently selected from hydrogen,C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5 or 6-membered heteroaryl, 4-6membered heterocycloalkyl, C₁₋₄ haloalkyl, C₂₋₄ alkenyl, or C₂₋₄alkynyl, wherein the C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5 or6-membered heteroaryl, 4-6 membered heterocycloalkyl, C₂₋₄ alkenyl, andC₂₋₄ alkynyl are optionally substituted with 1, 2 or 3 R^(q)substituents; R^(q) is selected from hydroxy, cyano, amino, halo, COOH,C₁₋₆ haloalkyl, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylthio, C₅₋₆ aryl, 5-6membered heteroaryl, 4-6 membered heterocycloalkyl, C₃₋₆ cycloalkyl,NHR⁸, NR⁸R⁸, and C₁₋₄ haloalkoxy, wherein the C₁₋₆ alkyl, C₅₋₆ aryl,C₃₋₆ cycloalkyl, 4-6 membered heterocycloalkyl, and 5-6 memberedheteroaryl are optionally substituted with halo, hydroxy, cyano, COOH,amino, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₅₋₆aryl, C₃₋₁₀ cycloalkyl, 5-6 membered heteroaryl and 4-6 memberedheterocycloalkyl; R⁸ is C₁₋₆ alkyl.

In an embodiment of the present disclosure, there is provided a compoundof Formula V, their polymorphs, stereoisomers, tautomers, prodrugs,solvates, and pharmaceutically acceptable salts thereof, wherein R₅ isselected from C₁₋₄ alkyl, cyano, or C₁₋₄ haloalkyl; R₄ is selected fromhydrogen, hydroxyl, C₁₋₆ alkyl, amino; R_(a1), R_(b1), and R_(c1) areindependently selected from hydrogen or C₁₋₆ alkyl; R₃ is independentlyselected from hydrogen, halo, C(O)OR^(a), C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₆₋₁₀ aryl, or C₃₋₁₀cycloalkyl; R₁, R₂, R₆, and R₇ are independently selected from hydrogen,halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl, 4-10membered heterocycloalkyl, CN, NO₂, OR^(a), SR^(a), NHOR^(a), C(O)R^(a),C(O)NR^(a)R^(a), C(O)OR^(a), OC(O)R^(a), OC(O)NR^(a)R^(a), NHR^(a),NR^(a)R^(a), NR^(a)C(O)R^(a), NR^(a)C(O)OR^(a), NR^(a)C(O)NR^(a)R^(a),C(═NR^(a))R^(a), C(═NR^(a))NR^(a)R^(a), NR^(a)C(═NR^(a))NR^(a)R^(a),NR^(a)S(O)R^(a), NR^(a)S(O)₂R^(a), NR^(a)S(O)₂NR^(a)R^(a), S(O)R^(a),S(O)NR^(a)R^(a), S(O)₂R^(a), or S(O)₂NR^(a)R^(a), wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14membered heteroaryl, 4-10 membered heterocycloalkyl, are independentlyoptionally substituted with 1, 2, 3, or 4 R^(b) substituents; R^(a) isselected from hydrogen, cyano, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, or4-10 membered heterocycloalkyl, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl are independently optionally substitutedwith 1, 2, 3, 4, or 5 R^(d) substituents; R^(b) is selected from halo,hydroxy, cyano, amino, nitro, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, NHOR^(c), OR^(c),SR^(c), C(O)R^(c), C(O)NR^(c)R^(c), C(O)OR^(c), OC(O)R^(c),OC(O)NR^(c)R^(c), C(═NR^(c))NR^(c)R^(c), NR^(c)C(═NR^(c))NR^(c)R^(c),NHR^(c), NR^(c)R^(c), NR^(c)C(O)R^(c), NR^(c)C(O)OR^(c),NR^(c)C(O)NR^(c)R^(c), NR^(c)S(O)R^(c), NR^(c)S(O)₂R^(c),NR^(c)S(O)₂NR^(c)R^(c), S(O)R^(c), S(O)NR^(c)R^(c), S(O)₂R^(c) orS(O)₂NR^(c)R^(c); wherein the C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, or 4-10 membered heterocycloalkyl are optionallysubstituted with 1, 2, or 3 R^(d) substituents; R^(d) is selected fromcyano, amino, C₁₋₆ alkyl, C₁₋₆haloalkyl, halo, C₆₋₁₀ aryl, 5-10 memberedheteroaryl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, NHOR^(e),OR^(e), SR^(e), C(O)R^(e), C(O)NR^(e)R^(e), C(O)OR^(e), OC(O)R^(e),OC(O)NR^(e)R^(e), NHR^(e), NR^(e)R^(e), NR^(e)C(O)R^(e),NR^(e)C(O)NR^(e)R^(e), NR^(e)C(O)OR^(e), C(═NR^(e))NR^(e)R^(e),NR^(e)C(═NR^(e))NR^(e)R^(e), NR^(e)C(═NOH)NR^(e)R^(e),NR^(e)C(═NCN)NR^(e)R^(e), S(O)R^(e), S(O)NR^(e)R^(e), S(O)₂R^(e),NR^(e)S(O)₂R^(e), NR^(e)S(O)₂NR^(e)R^(e), or S(O)₂NR^(e)R^(e), whereinthe C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,C₃₋₁₀ cycloalkyl, or 4-10 membered heterocycloalkyl are optionallysubstituted with 1, 2, or 3 R^(f) substituents; R^(c) is selected fromhydrogen, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, are optionally substituted with 1, 2, 3, 4, or 5 R^(f)substituent; R^(f) is selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, halogen, CN, NHOR^(g),OR^(g), SR^(g), C(O)R^(g), C(O)NR^(g)R^(g), C(O)OR^(g), OC(O)R^(g),OC(O)NR^(g)R^(g), NHR^(g), NR^(g)R^(g), NR^(g)C(O)R^(g),NR^(g)C(O)NR^(g)R^(g), NR^(g)C(O)OR^(g), C(═NR^(g))NR^(g)R^(g),NR^(g)C(═NR^(g))NR^(g)R^(g), S(O)R^(g), S(O)NR^(g)R^(g), S(O)₂R^(g),NR^(g)S(O)₂R^(g), NR^(g)S(O)₂NR^(g)R^(g), or S(O)₂NR^(g)R^(g); whereinthe C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, or 4-10 memberedheterocycloalkyl are optionally substituted with 1, 2, 3, 4, or 5 R^(n)substituents; R^(n) is selected from cyano, halo, C₁₋₄ alkyl, C₃₋₁₀cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 memberedheteroaryl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl,R^(o), NHOR^(o), OR^(o), SR^(o), C(O)R^(o), C(O)NR^(o)R^(o), C(O)OR^(o),OC(O)R^(o), OC(O)NR^(o)R^(o), NHR^(o), NR^(o)R^(o), NR^(o)C(O)R^(o),NR^(o)C(O)NR^(o)R^(o), NR^(o)C(O)OR^(o), C(═NR)NR^(o)R^(o),NR^(o)C(═NR^(o))NR^(o)R^(o), S(O)R^(o), S(O)NR^(o)R^(o), S(O)₂R^(o),NR^(o)S(O)₂R^(o), NR^(o)S(O)₂NR^(o)R^(o), or S(O)₂NR^(o)R^(o), whereinthe C₁₋₄ alkyl, C₃₋₁₀ cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀aryl, 5-6 membered heteroaryl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl and C₁₋₄ haloalkyl are optionally substituted with 1, 2 or 3R^(q) substituents; R^(g) is selected from hydrogen, C₁₋₆ alkyl, C₁₋₄haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl wherein theC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl are optionallysubstituted with 1, 2, or 3 R^(p) substituents; R^(p) is selected fromhalo, cyano, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, NHOR^(r), OR^(r), SR^(r), C(O)R^(r),C(O)NR^(r)R^(r), C(O)OR^(r), OC(O)R^(r), OC(O)NR^(r)R^(r), NHR^(r),NR^(r)R^(r), NR^(r)C(O)R^(r), NR^(r)C(O)NR^(r)R^(r), NR^(r)C(O)OR^(r),C(═NR)NR^(r), NR^(r)C(═NR^(r))NR^(r)R^(r), NR^(r)C(═NOH)NR^(r)R^(r),NR^(r)C(═NCN)NR^(r)R^(r), S(O)R^(r), S(O)NR^(r)R^(r), S(O)₂R^(r),NR^(r)S(O)₂R^(r), NR^(r)S(O)₂NR^(r)R^(r) or S(O)₂NR^(r)R^(r), whereinthe C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, are optionally substituted with 1, 2 or 3R^(q) substituents; R^(e), R^(i), R^(k), R^(o) and R^(r) areindependently selected from hydrogen, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀aryl, 5 or 6-membered heteroaryl, 4-6 membered heterocycloalkyl, C₁₋₄haloalkyl, C₂₋₄ alkenyl, or C₂₋₄ alkynyl, wherein the C₁₋₄ alkyl, C₃₋₆cycloalkyl, C₆₋₁₀ aryl, 5 or 6-membered heteroaryl, 4-6 memberedheterocycloalkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl are optionallysubstituted with 1, 2 or 3 R^(q) substituents; R^(q) is selected fromhydroxy, cyano, amino, halo, COOH, C₁₋₆ haloalkyl, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ alkylthio, C₅₋₆ aryl, 5-6 membered heteroaryl, 4-6 memberedheterocycloalkyl, C₃₋₆ cycloalkyl, NHR⁸, NR⁸R⁸, and C₁₋₄ haloalkoxy,wherein the C₁₋₆ alkyl, C₅₋₆ aryl, C₃₋₆ cycloalkyl, 4-6 memberedheterocycloalkyl, and 5-6 membered heteroaryl are optionally substitutedwith halo, hydroxy, cyano, COOH, amino, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄haloalkyl, C₁₋₄ haloalkoxy, C₅₋₆ aryl, C₃₋₁₀ cycloalkyl, 5-6 memberedheteroaryl and 4-6 membered heterocycloalkyl; R⁸ is C₁₋₆ alkyl.

In an embodiment of the present disclosure, there is provided a compoundof Formula VI

their polymorphs, stereoisomers, tautomers, prodrugs, solvates, andpharmaceutically acceptable salts thereof, wherein R₅ is selected fromC₁₋₄ alkyl, cyano, or C₁₋₄ haloalkyl; R₄ is selected from hydrogen,hydroxyl, C₁₋₆ alkyl, amino, —C(O)OR_(a1), C(O)NR_(b1)R_(c1), C₅₋₆ aryl,or C₁₋₆ heteroaryl; wherein C₁₋₆ alkyl is optionally substituted withone or more of the groups selected from the group consisting ofhydrogen, hydroxyl, amino, —C(O)OR_(a1), C(O)NR_(b1)R_(c1), C₅₋₆ aryl,and C₁₋₆ heteroaryl; R_(a1), R_(b1), and R_(c1) are independentlyselected from hydrogen or C₁₋₆ alkyl; R₁, R₂, R₃, R₆, and R₇ areindependently selected from hydrogen, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-14 memberedheteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-,CN, NO₂, OR^(a), SR^(a), NHOR^(a), C(O)R^(a), C(O)NR^(a)R^(a),C(O)OR^(a), OC(O)R^(a), OC(O)NR^(a)R^(a), NHR^(a), NR^(a)R^(a),NR^(a)C(O)R^(a), NR^(a)C(O)OR^(a), NR^(a)C(O)NR^(a)R^(a),C(═NR^(a))R^(a), C(═NR^(a))NR^(a)R^(a), NR^(a)C(═NR^(a))NR^(a)R^(a),NR^(a)S(O)R^(a), NR^(a)S(O)₂R^(a), NR^(a)S(O)₂NR^(a)R^(a), S(O)R^(a),S(O)NR^(a)R^(a), S(O)₂R^(a), or S(O)₂NR^(a)R^(a), wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-14 membered heteroaryl)-C₁₋₄alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, areindependently optionally substituted with 1, 2, 3, or 4 R^(b)substituents; R^(a) is selected from hydrogen, cyano, C₁₋₆ alkyl, C₁₋₄haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, or (4-10 membered heterocycloalkyl)-C₁₋₄alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- are independently optionally substitutedwith 1, 2, 3, 4, or 5 R^(d) substituents; R^(b) is selected from halo,hydroxy, cyano, amino, nitro, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, NHOR^(c), OR^(c),SR^(c), C(O)R^(c), C(O)NR^(c)R^(c), C(O)OR^(c), OC(O)R^(c),OC(O)NR^(c)R^(c), C(═NR^(c))NR^(c)R^(c), NR^(c)C(═NR^(c))NR^(c)R^(c),NHR^(c), NR^(c)R^(c), NR^(c)C(O)R^(c), NR^(c)C(O)OR^(c),NR^(c)C(O)NR^(c)R^(c), NR^(c)S(O)R^(c), NR^(c)S(O)₂R^(c),NR^(c)S(O)₂NR^(c)R^(c), S(O)R^(c), S(O)NR^(c)R^(c), S(O)₂R^(c) orS(O)₂NR^(c)R^(c); wherein the C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are optionallysubstituted with 1, 2, or 3 R^(d) substituents; R^(d) is selected fromcyano, amino, C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo, C₆₋₁₀ aryl, 5-10membered heteroaryl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-,NHOR^(e), OR^(e), SR^(e), C(O)R^(e), C(O)NR^(e)R^(e), C(O)OR^(e),OC(O)R^(e), OC(O)NR^(e)R^(e), NHR^(e), NR^(e)R^(e), NR^(e)C(O)R^(e),NR^(e)C(O)NR^(e)R^(e), NR^(e)C(O)OR^(e), C(═NR^(e))NR^(e)R^(e),NR^(e)C(═NR^(e))NR^(e)R^(e), NR^(e)C(═NOH)NR^(e)R^(e),NR^(e)C(═NCN)NR^(e)R^(e), S(O)R^(e), S(O)NR^(e)R^(e), S(O)₂R^(e),NR^(e)S(O)₂R^(e), NR^(e)S(O)₂NR^(e)R^(e), or S(O)₂NR^(e)R^(e), whereinthe C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are optionallysubstituted with 1, 2, or 3 R^(f) substituents; R^(c) is selected fromhydrogen, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, or (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10membered heterocycloalkyl)-C₁₋₄ alkyl- are optionally substituted with1, 2, 3, 4, or 5 R^(f) substituent; R^(f) is selected from C₁₋₄ alkyl,C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-,halogen, CN, NHOR^(g), OR^(g), SR^(f), C(O)R^(g), C(O)NR^(g)R^(g),C(O)OR^(g), OC(O)R^(g), OC(O)NR^(g)R^(g), NHR^(g), NR^(g)R^(g),NR^(g)C(O)R^(g), NR^(g)C(O)NR^(g)R^(g), NR^(g)C(O)OR^(g),C(═NR^(g))NR^(g)R^(g), NR^(g)C(═NR^(g))NR^(g)R^(g), S(O)R^(g),S(O)NR^(g)R^(g), S(O)₂R^(g), NR^(g)S(O)₂R^(g), NR^(g)S(O)₂NR^(g)R^(g),or S(O)₂NR^(g)R^(g); wherein the C₁₋₄ alkyl, C₁₋₄haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are optionallysubstituted with 1, 2, 3, 4, or 5 R^(n) substituents; R^(n) is selectedfrom cyano, halo, C₁₋₄ alkyl, C₃₋₁₀ cycloalkyl, 4-7 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-6 membered heteroaryl)-C₁₋₄alkyl-, (4-7 membered heterocycloalkyl)-C₁₋₄ alkyl-, C₁₋₆ haloalkoxy,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl, R^(o), NHOR^(o), OR^(o),SR^(o), C(O)R^(o), C(O)NR^(o)R^(o), C(O)OR^(o), OC(O)R^(o),OC(O)NR^(o)R^(o), NHR^(o), NR^(o)R^(o), NR^(o)C(O)R^(o),NR^(o)C(O)NR^(o)R^(o), NR^(o)C(O)OR^(o), C(═NR)NR^(o)R^(o),NR^(o)C(═NR^(o))NR^(o)R^(o), S(O)R^(o), S(O)NR^(o)R^(o), S(O)₂R^(o),NR^(o)S(O)₂R^(o), NR^(o)S(O)₂NR^(o)R^(o), or S(O)₂NR^(o)R^(o), whereinthe C₁₋₄ alkyl, C₃₋₁₀ cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀aryl, 5-6 membered heteroaryl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-6 membered heteroaryl)-C₁₋₄ alkyl-, (4-7membered heterocycloalkyl)-C₁₋₄ alkyl-, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl,C₂₋₆ alkynyl and C₁₋₄haloalkyl are optionally substituted with 1, 2 or 3R^(q) substituents; R^(g) is selected from hydrogen, C₁₋₆ alkyl, C₁₋₄haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, or (4-10 membered heterocycloalkyl)-C₁₋₄alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- are optionally substituted with 1, 2, or 3R^(p) substituents; R^(p) is selected from halo, cyano, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, NHOR^(r), OR^(r), SR^(r), C(O)R^(r),C(O)NR^(r)R^(r), C(O)OR^(r), OC(O)R^(r), OC(O)NR^(r)R^(r), NHR^(r),NR^(r)R^(r), NR^(r)C(O)R^(r), NR^(r)C(O)NR^(r)R^(r), NR^(r)C(O)OR^(r),C(═NR^(r))NR^(r)R^(r), NR^(r)C(═NR^(r))NR^(r)R^(r),NR^(r)C(═NOH)NR^(r)R^(r), NR^(r)C(═NCN)NR^(r)R^(r), S(O)R^(r),S(O)NR^(r)R^(r), S(O)₂R^(r), NR^(r)S(O)₂R^(r), NR^(r)S(O)₂NR^(r)R^(r) orS(O)₂NR^(r)R^(r), wherein the C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-are optionally substituted with 1, 2 or 3 R^(q) substituents; R^(e),R^(i), R^(k), R^(o) and R^(r) are independently selected from hydrogen,C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5 or 6-membered heteroaryl, 4-6membered heterocycloalkyl, C₁₋₄ haloalkyl, C₂₋₄ alkenyl, or C₂₋₄alkynyl, wherein the C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5 or6-membered heteroaryl, 4-6 membered heterocycloalkyl, C₂₋₄ alkenyl, andC₂₋₄ alkynyl are optionally substituted with 1, 2 or 3 R^(q)substituents; R^(q) is selected from hydroxy, cyano, amino, halo, COOH,C₁₋₆ haloalkyl, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylthio, C₅₋₆ aryl, 5-6membered heteroaryl, 4-6 membered heterocycloalkyl, C₃₋₆ cycloalkyl,NHR⁸, NR⁸R⁸, and C₁₋₄ haloalkoxy, wherein the C₁₋₆ alkyl, C₅₋₆ aryl,C₃₋₆ cycloalkyl, 4-6 membered heterocycloalkyl, and 5-6 memberedheteroaryl are optionally substituted with halo, hydroxy, cyano, COOH,amino, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₅₋₆aryl, C₃₋₁₀ cycloalkyl, 5-6 membered heteroaryl and 4-6 memberedheterocycloalkyl; R⁸ is C₁₋₆ alkyl.

In an embodiment of the present disclosure, there is provided a compoundof Formula VI, their polymorphs, stereoisomers, tautomers, prodrugs,solvates, and pharmaceutically acceptable salts thereof, wherein R₅ isselected from C₁₋₄ alkyl, cyano, or C₁₋₄ haloalkyl; R⁴ is selected fromhydrogen, hydroxyl, C₁₋₆ alkyl, amino; R_(a1), R_(b1), and R_(c1) areindependently selected from hydrogen or C₁₋₆ alkyl; R₃ is independentlyselected from hydrogen, halo, C(O)OR^(a), C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₆₋₁₀ aryl, or C₃₋₁₀cycloalkyl; R₁, R₂, R₆, and R₇ are independently selected from hydrogen,halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl, 4-10membered heterocycloalkyl, CN, NO₂, OR^(a), SR^(a), NHOR^(a), C(O)R^(a),C(O)NR^(a)R^(a), C(O)OR^(a), OC(O)R^(a), OC(O)NR^(a)R^(a), NHR^(a),NR^(a)R^(a), NR^(a)C(O)R^(a), NR^(a)C(O)OR^(a), NR^(a)C(O)NR^(a)R^(a),C(═NR^(a))R^(a), C(═NR^(a))NR^(a)R^(a), NR^(a)C(═NR^(a))NR^(a)R^(a),NR^(a)S(O)R^(a), NR^(a)S(O)₂R^(a), NR^(a)S(O)₂NR^(a)R^(a), S(O)R^(a),S(O)NR^(a)R^(a), S(O)₂R^(a), or S(O)₂NR^(a)R^(a), wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14membered heteroaryl, 4-10 membered heterocycloalkyl, are independentlyoptionally substituted with 1, 2, 3, or 4 R^(b) substituents; R^(a) isselected from hydrogen, cyano, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, or4-10 membered heterocycloalkyl, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl are independently optionally substitutedwith 1, 2, 3, 4, or 5 R^(d) substituents; R^(b) is selected from halo,hydroxy, cyano, amino, nitro, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, NHOR^(c), OR^(c),SR^(c), C(O)R^(c), C(O)NR^(c)R^(c), C(O)OR^(c), OC(O)R^(c),OC(O)NR^(c)R^(c), C(═NR^(c))NR^(c)R^(c), NR^(c)C(═NR^(c))NR^(c)R^(c),NHR^(c), NR^(c)R^(c), NR^(c)C(O)R^(c), NR^(c)C(O)OR^(c),NR^(c)C(O)NR^(c)R^(c), NR^(c)S(O)R^(c), NR^(c)S(O)₂R^(c),NR^(c)S(O)₂NR^(c)R^(c), S(O)R^(c), S(O)NR^(c)R^(c), S(O)₂R^(c) orS(O)₂NR^(c)R^(c); wherein the C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, or 4-10 membered heterocycloalkyl are optionallysubstituted with 1, 2, or 3 R^(d) substituents; R^(d) is selected fromcyano, amino, C₁₋₆ alkyl, C₁₋₆haloalkyl, halo, C₆₋₁₀ aryl, 5-10 memberedheteroaryl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, NHOR^(e),OR^(e), SR^(e), C(O)R^(e), C(O)NR^(e)R^(e), C(O)OR^(e), OC(O)R^(e),OC(O)NR^(e)R^(e), NHR^(e), NR^(e)R^(e), NR^(e)C(O)R^(e),NR^(e)C(O)NR^(e)R^(e), NR^(e)C(O)OR^(e), C(═NR^(e))NR^(e)R^(e),NR^(e)C(═NR^(e))NR^(e)R^(e), NR^(e)C(═NOH)NR^(e)R^(e),NR^(e)C(═NCN)NR^(e)R^(e), S(O)R^(e), S(O)NR^(e)R^(e), S(O)₂R^(e),NR^(e)S(O)₂R^(e), NR^(e)S(O)₂NR^(e)R^(e), or S(O)₂NR^(e)R^(e), whereinthe C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,C₃₋₁₀ cycloalkyl, or 4-10 membered heterocycloalkyl are optionallysubstituted with 1, 2, or 3 R^(f) substituents; R^(c) is selected fromhydrogen, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, are optionally substituted with 1, 2, 3, 4, or 5 R^(f)substituent; R^(f) is selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, halogen, CN, NHOR^(g),OR^(g), SR^(g), C(O)R^(g), C(O)NR^(g)R^(g), C(O)OR^(g), OC(O)R^(g),OC(O)NR^(g)R^(g), NHR^(g), NR^(g)R^(g), NR^(g)C(O)R^(g),NR^(g)C(O)NR^(g)R^(g), NR^(g)C(O)OR^(g), C(═NR^(g))NR^(g)R^(g),NR^(g)C(═NR^(g))NR^(g)R^(g), S(O)R^(g), S(O)NR^(g)R^(g), S(O)₂R^(g),NR^(g)S(O)₂R^(g), NR^(g)S(O)₂NR^(g)R^(g), or S(O)₂NR^(g)R^(g); whereinthe C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, or 4-10 memberedheterocycloalkyl are optionally substituted with 1, 2, 3, 4, or 5 R^(n)substituents; R^(n) is selected from cyano, halo, C₁₋₄ alkyl, C₃₋₁₀cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 memberedheteroaryl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl,R^(o), NHOR^(o), OR^(o), SR^(o), C(O)R^(o), C(O)NR^(o)R^(o), C(O)OR^(o),OC(O)R^(o), OC(O)NR^(o)R^(o), NHR^(o), NR^(o)R^(o), NR^(o)C(O)R^(o),NR^(o)C(O)NR^(o)R^(o), NR^(o)C(O)OR^(o), C(═NR)NR^(o)R^(o),NR^(o)C(═NR^(o))NR^(o)R^(o), S(O)R^(o), S(O)NR^(o)R^(o), S(O)₂R^(o),NR^(o)S(O)₂R^(o), NR^(o)S(O)₂NR^(o)R^(o), or S(O)₂NR^(o)R^(o), whereinthe C₁₋₄ alkyl, C₃₋₁₀ cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀aryl, 5-6 membered heteroaryl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl and C₁₋₄ haloalkyl are optionally substituted with 1, 2 or 3R^(q) substituents; R^(g) is selected from hydrogen, C₁₋₆ alkyl, C₁₋₄haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl wherein theC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl are optionallysubstituted with 1, 2, or 3 R^(p) substituents; R^(p) is selected fromhalo, cyano, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆alkenyl,C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, NHOR^(r), OR^(r), SR^(r), C(O)R^(r),C(O)NR^(r)R^(r), C(O)OR^(r), OC(O)R^(r), OC(O)NR^(r)R^(r), NHR^(r),NR^(r)R^(r), NR^(r)C(O)R^(r), NR^(r)C(O)NR^(r)R^(r), NR^(r)C(O)OR^(r),C(═NR^(r))NR^(r)R^(r), NR^(r)C(═NR^(r))NR^(r)R^(r),NR^(r)C(═NOH)NR^(r)R^(r), NR^(r)C(═NCN)NR^(r)R^(r), S(O)R^(r),S(O)NR^(r)R^(r), S(O)₂R^(r), NR^(r)S(O)₂R^(r), NR^(r)S(O)₂NR^(r)R^(r) orS(O)₂NR^(r)R^(r), wherein the C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, are optionallysubstituted with 1, 2 or 3 R^(q) substituents; R^(e), R^(i), R^(k),R^(o) and R^(r) are independently selected from hydrogen, C₁₋₄ alkyl,C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5 or 6-membered heteroaryl, 4-6 memberedheterocycloalkyl, C₁₋₄ haloalkyl, C₂₋₄ alkenyl, or C₂₋₄ alkynyl, whereinthe C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5 or 6-membered heteroaryl,4-6 membered heterocycloalkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl areoptionally substituted with 1, 2 or 3 R^(q) substituents; R^(q) isselected from hydroxy, cyano, amino, halo, COOH, C₁₋₆ haloalkyl, C₁₋₆alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylthio, C₅₋₆ aryl, 5-6 membered heteroaryl,4-6 membered heterocycloalkyl, C₃₋₆ cycloalkyl, NHR⁸, NR⁸R⁸, and C₁₋₄haloalkoxy, wherein the C₁₋₆ alkyl, C₅₋₆ aryl, C₃₋₆ cycloalkyl, 4-6membered heterocycloalkyl, and 5-6 membered heteroaryl are optionallysubstituted with halo, hydroxy, cyano, COOH, amino, C₁₋₄ alkyl, C₁₋₄alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₅₋₆ aryl, C₃₋₁₀ cycloalkyl,5-6 membered heteroaryl and 4-6 membered heterocycloalkyl; R⁸ is C₁₋₆alkyl

In an embodiment, the present disclosure relates to compounds of FormulaI, Formula II, Formula III, Formula IV, Formula V, Formula VI, or itspolymorphs, stereoisomers, tautomers, prodrugs, solvates, andpharmaceutically acceptable salts thereof, which is selected from agroup consisting of:

-   (S)-1-((7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)    piperidine-2-carboxylic acid (1),-   N-(2-(((5-methoxy-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)    methyl)amino)ethyl)acetamide (2),-   (S)-1-((7-((3-(1-(3-(3,3-difluoropyrrolidin-1-yl)propyl)-1H-indol-4-yl)-2-methylbenzyl)oxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylic    acid (3),-   (S)-1-((6-methyl-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylic    acid (4),-   (S)-1-((6-chloro-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylic    acid (5),-   Methyl    7-(((2-acetamidoethyl)amino)methyl)-4-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-indene-5-carboxylate    (6),-   (S)-1-((7-((3′-(3-(3,3-difluoropyrrolidin-1-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-methoxy-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylic    acid (7),-   (S)-1-((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylic    acid (8),-   (S)-1-((5-((5-fluoropyridin-3-yl)methoxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylic    acid (9)-   N-(2-(((5-((5-fluoropyridin-3-yl)methoxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)amino)ethyl)acetamide    (10)-   (S)-5-((5-methoxy-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)-5-azaspiro[2.4]heptane-6-carboxylic    acid (11)-   (S)-1-((7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-5-(2,2,2-trifluoroethoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylic    acid (12)-   N-(2-(((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)amino)ethyl)-N-methylacetamide    (13)-   N-(2-(((5-(1-(3-cyanophenyl)ethoxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)amino)ethyl)acetamide    (14)-   N-(1-((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidin-3-yl)acetamide    (15)-   N-(2-(((7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)amino)ethyl)acetamide    (16)-   6-((7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)-2-oxa-6-azaspiro[3.3]heptane    (17)-   2-(hydroxymethyl)-2-(((7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)amino)propane-1,3-diol    (18)-   1-(((7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)amino)cyclopropane-1-carboxylic    acid (19)-   ((7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)glycine    (20)-   3-(((7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)amino)propanoic    acid (21)-   N-methyl-N-((7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)glycine    (22)-   3-(((7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)amino)butanoic    acid (23)-   ((7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)alanine    (24)-   (2S,4R)-4-hydroxy-1-((5-methoxy-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)pyrrolidine-2-carboxylic    acid (25)-   (S)-1-((5-methoxy-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylic    acid (26)-   1-((4-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-5,6,7,8-tetrahydronaphthalen-1-yl)methyl)piperidine-2-carboxylic    acid (27)-   N-(2-(((6-methyl-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)amino)ethyl)acetamide    (28)-   (2S,4R)-4-hydroxy-1-((6-methyl-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)pyrrolidine-2-carboxylic    acid (29)-   N-(2-(((6-chloro-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)amino)ethyl)acetamide    (30)-   (2S,4R)-1-((6-chloro-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)-4-hydroxypyrrolidine-2-carboxylic    acid (31)-   N-(2-(((7-((3′-(3-(3,3-difluoropyrrolidin-1-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-methoxy-2,3-dihydro-1H-inden-4-yl)methyl)amino)ethyl)acetamide    (32)-   (2S,4R)-1-((7-((3′-(3-(3,3-difluoropyrrolidin-1-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-methoxy-2,3-dihydro-1H-inden-4-yl)methyl)-4-hydroxypyrrolidine-2-carboxylic    acid (33)-   N-(2-(((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)amino)ethyl)acetamide    (34)-   (2S,4R)-1-((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)-4-hydroxypyrrolidine-2-carboxylic    acid (35)-   (S)-1-((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylic    acid (36)-   (S)-1-((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxamide    (37)-   3-(((4-(((1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)amino)methyl)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)benzonitrile    (38)-   3-(((4-((2-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)benzonitrile    (39)-   3-(((4-((3-hydroxypiperidin-1-yl)methyl)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)benzonitrile    (40)-   ((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)glycine    (41)-   (S)-5-((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)-5-azaspiro[2.4]heptane-6-carboxylic    acid (42)-   rac-(1R,6S)-2-((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)    methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)-2-azabicyclo[4.1.0]heptane-1-carboxylic    acid (cis, racemic) (43)-   4-(((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)    methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)amino)butanoic acid (44)-   (1R,6S)-2-((5-methoxy-7-((2-methyl-[1,1′-biphenyl]-3-yl)    methoxy)-2,3-dihydro-1H-inden-4-yl)    methyl)-2-azabicyclo[4.1.0]heptane-1-carboxylic acid (cis, racemic)    (45)-   (S)-1-((5-((5-cyanopyridin-3-yl)methoxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)    methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylic    acid (46)-   (2S,4R)-1-((5-((5-cyanopyridin-3-yl)methoxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)-4-hydroxypyrrolidine-2-carboxylic    acid (47)-   N-(2-(((5-((5-cyanopyridin-3-yl)methoxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)amino)ethyl)acetamide    (48)-   5-(((4-(((1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)amino)methyl)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)nicotinonitrile    (49)-   (S)-4-((5-((5-cyanopyridin-3-yl)methoxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)morpholine-3-carboxylicacid    (50)-   rac-(1R,6S)-2-((5-((5-cyanopyridin-3-yl)methoxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)-2-azabicyclo[4.1.0]heptane-1-carboxylic    acid (cis, racemic) (51)-   (S)-5-((5-((5-cyanopyridin-3-yl)methoxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)-5-azaspiro[2.4]heptane-6-carboxylic    acid (52)-   N-(2-(((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)(methyl)amino)ethyl)acetamide    (53)-   N-(2-(((5-((4-cyanobenzyl)oxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)amino)ethyl)acetamide    (54)-   (S)-1-((7-((2-cyano-[1,1′-biphenyl]-3-yl)methoxy)-5-methoxy-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylic    acid (55)-   N-(2-(((7-((2-cyano-[1,1′-biphenyl]-3-yl)methoxy)-5-methoxy-2,3-dihydro-1H-inden-4-yl)methyl)amino)ethyl)acetamide    (56)-   (2S,4R)-1-((7-((2-cyano-[1,1′-biphenyl]-3-yl)methoxy)-5-methoxy-2,3-dihydro-1H-inden-4-yl)methyl)-4-hydroxypyrrolidine-2-carboxylic    acid (57)-   3-(((7-(((1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)amino)methyl)-6-methoxy-2,3-dihydro-1H-inden-4-yl)oxy)methyl)-[1,1′-biphenyl]-2-carbonitrile    (58)-   (S)-4-((7-((2-cyano-[1,1′-biphenyl]-3-yl)methoxy)-5-methoxy-2,3-dihydro-1H-inden-4-yl)methyl)morpholine-3-carboxylic    acid (59)-   ((7-((2-cyano-[1,1′-biphenyl]-3-yl)methoxy)-5-methoxy-2,3-dihydro-1H-inden-4-yl)methyl)glycine    (60)-   (S)-5-((7-((2-cyano-[1,1′-biphenyl]-3-yl)methoxy)-5-methoxy-2,3-dihydro-1H-inden-4-yl)methyl)-5-azaspiro[2.4]heptane-6-carboxylic    acid (61)-   rac-(1R,6S)-2-((7-((2-cyano-[1,1′-biphenyl]-3-yl)methoxy)-5-methoxy-2,3-dihydro-1H-inden-4-yl)methyl)-2-azabicyclo[4.1.0]heptane-1-carboxylic    acid (cis, racemic) (62)-   2-(1-((7-((2-cyano-[1,1′-biphenyl]-3-yl)methoxy)-5-methoxy-2,3-dihydro-1H-inden-4-yl)methyl)piperidin-2-yl)acetic    acid (63)-   N-(2-(((7-((2-cyano-[1,1′-biphenyl]-3-yl)methoxy)-5-methoxy-2,3-dihydro-1H-inden-4-yl)methyl)(methyl)amino)ethyl)-N-methylacetamide    (64)-   5-((4-(((2-acetamidoethyl)amino)methyl)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)pentanoic    acid (65)-   5-((4-(((2-acetamidoethyl)amino)methyl)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)pentanamide    (66)-   (S)-1-((5-(4-carboxybutoxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylic    acid (67)-   (S)-1-((5-((5-amino-5-oxopentyl)oxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylic    acid (68)-   (S)-1-((5-((5-cyanopyridin-3-yl)methoxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)    methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylic    acid (69)-   (2S,4R)-1-((7-((2-cyano-[1,1′-biphenyl]-3-yl)methoxy)-5-((5-cyanopyridin-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)-4-hydroxypyrrolidine-2-carboxylic    acid (70)-   (R)-1-((7-((2-cyano-[1,1′-biphenyl]-3-yl)methoxy)-5-((5-cyanopyridin-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-3-carboxylic    acid (71)-   rac-(1R,6S)-2-((7-((2-cyano-[1,1′-biphenyl]-3-yl)methoxy)-5-((5-cyanopyridin-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)-2-azabicyclo[4.1.0]heptane-1-carboxylic    acid (cis; racemic) (72)-   methyl    4-(((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylate    (73)-   4-(((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid (74)-   (S)-1-((5-methoxy-7-((2-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylic    acid (75)-   (2S,4R)-4-hydroxy-1-((5-methoxy-7-((2-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)pyrrolidine-2-carboxylic    acid (76)-   (2S)-1-((7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-5-((1-methylpiperidin-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylic    acid (77)-   (S)-1-((5-(4-carboxybutoxy)-7-((2-cyano-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylic    acid (78)-   N-(2-(((5-(4-cyanobutoxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)amino)ethyl)acetamide    (79)-   (S)-1-((5-(4-cyanobutoxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxamide    (80)-   (2S,4R)-1-((5-(4-cyanobutoxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)-4-hydroxypyrrolidine-2-carboxylic    acid (81)-   (S)-1-((5-(((1S,2R)-2-carboxycyclopropyl)methoxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylic    acid (82)-   (1R,2S)-2-(((4-(((2-acetamidoethyl)amino)methyl)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)cyclopropane-1-carboxylic    acid (83)-   (S)-1-((7-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylbenzyl)oxy)-5-methoxy-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylic    acid (84)-   (2S,4R)-1-((7-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylbenzyl)oxy)-5-methoxy-2,3-dihydro-1H-inden-4-yl)methyl)-4-hydroxypyrrolidine-2-carboxylic    acid (85)-   N-(2-(((5-((3-cyanobenzyl)oxy)-7-((2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)amino)ethyl)acetamide    (86)-   N-(2-(((5-((3-cyanobenzyl)oxy)-7-((4′-fluoro-2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)amino)ethyl)acetamide    (87)-   (S)-1-((5-((3-carbamoylbenzyl)oxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylic    acid (88)-   3-(((4-(aminomethyl)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)benzonitrile    (89)-   N-((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)    methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)acetamide (90)-   6-acetamido-N-((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)hexanamide    (91)-   3-(((4-((dimethylamino)methyl)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)benzonitrile    (92)-   5-(((4-(((2-acetamidoethyl)amino)methyl)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)nicotinic    acid (93)-   5-(((4-(((2-acetamidoethyl)amino)methyl)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)nicotinamide    (94)-   3-(((4-(((2-acetamidoethyl)amino)methyl)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)benzamide    (95)-   (S)-1-((3-methoxy-1-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)methyl)piperidine-2-carboxylic    acid (96)-   N-(2-(((3-methoxy-1-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)methyl)amino)ethyl)acetamide    (97)-   (S)-4-((5-methoxy-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)morpholine-3-carboxylic    acid (98)-   5-((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic    acid (99)

In an embodiment, the present disclosure relates to a process ofpreparation of compounds of Formula I, Formula II, Formula III, FormulaIV, Formula V, and Formula VI as described herein, or its polymorphs,stereoisomers, tautomers, prodrugs, solvates, and pharmaceuticallyacceptable salts thereof.

In an embodiment, the present disclosure relates to a process ofpreparation of Formula I, comprising steps of: (a) reacting compounds ofFormula I (a) with substituted amines to obtain compounds of Formula I

In an embodiment, the present disclosure relates to a process ofpreparation of Formula I, comprising steps of: (a) reacting compounds ofFormula I (a), wherein the X₁ of Formula I (a) and Formula I is selectedfrom —CH₂O—, —OCH₂—, —C(O)NH— or —NHC(O)—; R₄ of Formula I (a) andFormula I is selected from hydrogen, hydroxyl, C₁₋₆ alkyl, amino,—C(O)OR_(a1), C(O)NR_(b1)R_(c1), C₅₋₆ aryl, or C₁₋₆ heteroaryl, whereinC₁₋₆ alkyl is optionally substituted with one or more of the groupsselected from the group consisting of hydrogen, hydroxyl, amino,—C(O)OR_(a1), C(O)NR_(b1)R_(c1), C₅₋₆ aryl, and C₁₋₆ heteroaryl; R_(a1),R_(b1), and R_(c1) are independently selected from hydrogen or C₁₋₆alkyl; X of Formula I (a) and Formula I is selected from CR₃ or N; R₁,R₂, R₆, and R₇ of Formula I (a) and Formula I are independently selectedfrom hydrogen, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-14 membered heteroaryl)-C₁₋₄ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a), SR^(a),NHOR^(a), C(O)R^(a), C(O)NR^(a)R^(a), C(O)OR^(a), OC(O)R^(a),OC(O)NR^(a)R^(a), NHR^(a), NR^(a)R^(a), NR^(a)C(O)R^(a),NR^(a)C(O)OR^(a), NR^(a)C(O)NR^(a)R^(a), C(═NR^(a))R^(a),C(═NR^(a))NR^(a)R^(a), NR^(a)C(═NR^(a))NR^(a)R^(a), NR^(a)S(O)R^(a),NR^(a)S(O)₂R^(a), NR^(a)S(O)₂NR^(a)R^(a), S(O)R^(a), S(O)NR^(a)R^(a),S(O)₂R^(a), or S(O)₂NR^(a)R^(a), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-14 membered heteroaryl)-C₁₋₄ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, are independentlyoptionally substituted with 1, 2, 3, or 4 R^(b) substituents; R^(a) isselected from hydrogen, cyano, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, or (4-10membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are independentlyoptionally substituted with 1, 2, 3, 4, or 5 R^(d) substituents; R^(b)is selected from halo, hydroxy, cyano, amino, nitro, C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, NHOR^(c), OR^(c), SR^(c), C(O)R^(c),C(O)NR^(c)R^(c), C(O)OR^(c), OC(O)R^(c), OC(O)NR^(c)R^(c),C(═NR^(c))NR^(c)R^(c), NR^(c)C(═NR^(c))NR^(c)R^(c), NHR^(c),NR^(c)R^(c), NR^(c)C(O)R^(c), NR^(c)C(O)OR^(c), NR^(c)C(O)NR^(c)R^(c),NR^(c)S(O)R^(c), NR^(c)S(O)₂R^(c), NR^(c)S(O)₂NR^(c)R^(c), S(O)R^(c),S(O)NR^(c)R^(c), S(O)₂R^(c) or S(O)₂NR^(c)R^(c); wherein the C₁₋₄ alkyl,C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- are optionally substituted with 1, 2, or 3R^(d) substituents; R^(c) is selected from hydrogen, C₁₋₆ alkyl, C₁₋₄haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, or (4-10 membered heterocycloalkyl)-C₁₋₄alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- are optionally substituted with 1, 2, 3,4, or 5 R^(f) substituent; R^(d) is selected from cyano, amino, C₁₋₆alkyl, C₁₋₆ haloalkyl, halo, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, NHOR^(e), OR^(e), SR^(e),C(O)R^(e), C(O)NR^(e)R^(e), C(O)OR^(e), OC(O)R^(e), OC(O)NR^(e)R^(e),NHR^(e), NR^(e)R^(e), NR^(e)C(O)R^(e), NR^(e)C(O)NR^(e)R^(e),NR^(e)C(O)OR^(e), C(═NR^(e))NR^(e)R^(e), NR^(e)C(═NR^(e))NR^(e)R^(e),NR^(e)C(═NOH)NR^(e)R^(e), NR^(e)C(═NCN)NR^(e)R^(e), S(O)R^(e),S(O)NR^(e)R^(e), S(O)₂R^(e), NR^(e)S(O)₂R^(e), NR^(e)S(O)₂NR^(e)R^(e),or S(O)₂NR^(e)R^(e), wherein the C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- are optionally substituted with 1, 2, or 3R^(f) substituents; R^(f) is selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, halogen, CN, NHOR^(g),OR^(g), SR^(g), C(O)R^(g), C(O)NR^(g)R^(g), C(O)OR^(g), OC(O)R^(g),OC(O)NR^(g)R^(g), NHR^(g), NR^(g)R^(g), NR^(g)C(O)R^(g),NR^(g)C(O)NR^(g)R^(g), NR^(g)C(O)OR^(g), C(═NR^(g))NR^(g)R^(g),NR^(g)C(═NR^(g))NR^(g)R^(g), S(O)R^(g), S(O)NR^(g)R^(g), S(O)₂R^(g),NR^(g)S(O)₂R^(g), NR^(g)S(O)₂NR^(g)R^(g), or S(O)₂NR^(g)R^(g); whereinthe C₁₋₄ alkyl, C₁₋₄haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- are optionally substituted with 1, 2, 3,4, or 5 R^(n) substituents; R^(g) is selected from hydrogen, C₁₋₆ alkyl,C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, or (4-10 membered heterocycloalkyl)-C₁₋₄alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- are optionally substituted with 1, 2, or 3R^(p) substituents; R^(n) is selected from cyano, halo, C₁₋₄ alkyl,C₃₋₁₀ cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6membered heteroaryl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄alkyl-, (5-6 membered heteroaryl)-C₁₋₄ alkyl-, (4-7 memberedheterocycloalkyl)-C₁₋₄ alkyl-, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₄ haloalkyl, R^(o), NHOR^(o), OR^(o), SR^(o), C(O)R^(o),C(O)NR^(o)R^(o), C(O)OR^(o), OC(O)R^(o), OC(O)NR^(o)R^(o), NHR^(o),NR^(o)R^(o), NR^(o)C(O)R^(o), NR^(o)C(O)NR^(o)R^(o), NR^(o)C(O)OR^(o),C(═NR)NR^(o)R^(o), NR^(o)C(═NR^(o))NR^(o)R^(o), S(O)R^(o),S(O)NR^(o)R^(o), S(O)₂R^(o), NR^(o)S(O)₂R^(o), NR^(o)S(O)₂NR^(o)R^(o),or S(O)₂NR^(o)R^(o), wherein the C₁₋₄ alkyl, C₃₋₁₀ cycloalkyl, 4-7membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-6 memberedheteroaryl)-C₁₋₄ alkyl-, (4-7 membered heterocycloalkyl)-C₁₋₄ alkyl-,C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₄haloalkyl areoptionally substituted with 1, 2 or 3 R^(q) substituents; R^(p) isselected from halo, cyano, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, NHOR^(r), OR^(r), SR^(r),C(O)R^(r), C(O)NR^(r)R^(r), C(O)OR^(r), OC(O)R^(r), OC(O)NR^(r)R^(r),NHR^(r), NR^(r)R^(r), NR^(r)C(O)R^(r), NR^(r)C(O)NR^(r)R^(r),NR^(r)C(O)OR^(r), C(═NR^(r))NR^(r)R^(r), NR^(r)C(═NR^(r))NR^(r)R^(r),NR^(r)C(═NOH)NR^(r)R^(r), NR^(r)C(═NCN)NR^(r)R^(r), S(O)R^(r),S(O)NR^(r)R^(r), S(O)₂R^(r), NR^(r)S(O)₂R^(r), NR^(r)S(O)₂NR^(r)R^(r) orS(O)₂NR^(r)R^(r), wherein the C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-are optionally substituted with 1, 2 or 3 R^(q) substituents; R^(e),R^(i), R^(k), R^(o) and R^(r) are independently selected from hydrogen,C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5 or 6-membered heteroaryl, 4-6membered heterocycloalkyl, C₁₋₄ haloalkyl, C₂₋₄ alkenyl, or C₂₋₄alkynyl, wherein the C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5 or6-membered heteroaryl, 4-6 membered heterocycloalkyl, C₂₋₄ alkenyl, andC₂₋₄ alkynyl are optionally substituted with 1, 2 or 3 R^(q)substituents; R^(q) is selected from hydroxy, cyano, amino, halo, COOH,C₁₋₆ haloalkyl, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylthio, C₅₋₆ aryl, 5-6membered heteroaryl, 4-6 membered heterocycloalkyl, C₃₋₆ cycloalkyl,NHR⁸, NR⁸R⁸, and C₁₋₄ haloalkoxy, wherein the C₁₋₆ alkyl, C₅₋₆ aryl,C₃₋₆ cycloalkyl, 4-6 membered heterocycloalkyl, and 5-6 memberedheteroaryl are optionally substituted with halo, hydroxy, cyano, COOH,amino, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₅₋₆aryl, C₃₋₁₀ cycloalkyl, 5-6 membered heteroaryl and 4-6 memberedheterocycloalkyl; R⁸ is C₁₋₆ alkyl; m is 1 or 2; Ring A is selected fromsubstituted or unsubstituted C₅₋₁₀ aryl, substituted or unsubstitutedC₃₋₆ cycloalkyl, and substituted or unsubstituted 5-10 memberedmonocyclic or bicyclic saturated or unsaturated heterocyclic ring with1-3 heteroatoms selected from N, S or O; Ring B is selected from C₅₋₁₀aryl, C₃₋₆ cycloalkyl, 5-10 membered monocyclic or bicyclic saturated orunsaturated heterocyclic ring with 1-3 heteroatoms selected from N, S orO, with substituted amines in the presence of solvents to obtaincompounds of Formula I.

In an embodiment, the present disclosure relates to pharmaceuticalcomposition comprising a compound of Formula I, or Formula II, orFormula III, or Formula IV, or Formula V, or Formula VI as describedherein, or a pharmaceutically acceptable salt thereof together with apharmaceutically acceptable carrier, optionally in combination with oneor more other pharmaceutical compositions.

In another embodiment, the present disclosure relates to thepharmaceutical composition as described herein, wherein the compositionis in the form selected from the group consisting of a tablet, capsule,powder, syrup, solution, aerosol and suspension.

In an embodiment of the present disclosure, there is provided compoundsof Formula I, Formula II, Formula III, Formula IV, Formula V, andFormula VI or a pharmaceutically acceptable salt thereof as describedherein, wherein the pharmaceutically acceptable salt selected derivedfrom inorganic bases such as like Li, Na, K, Ca, Mg, Fe, Cu, Zn and Mn;salts of organic bases such as N, N′-diacetylethylenediamine, glucamine,triethylamine, choline, dicyclohexylamine, benzylamine, trialkylamine,thiamine, guanidine, diethanolamine, α-phenylethylamine, piperidine,morpholine, pyridine, hydroxyethylpyrrolidine, hydroxyethylpiperidine,ammonium, substituted ammonium salts, aluminum salts and the like. Saltsalso include amino acid salts such as glycine, alanine, cystine,cysteine, lysine, arginine, phenylalanine, and guanidine. Salts mayinclude acid addition salts where appropriate which are sulfates,nitrates, phosphates, perchlorates, borates, hydrohalides, acetates,tartrates, maleates, citrates, succinates, palmoates, methanesulfonates,tosylates, benzoates, salicylates, hydroxynaphthoates,benzenesulfonates, ascorbates, glycerophosphates, ketoglutarates.

In an embodiment, the present disclosure relates to a method for thetreatment and/or prevention of a proliferative disorder or cancercomprising administering to a subject suffering from the proliferativedisorder or cancer a therapeutically effective amount of the compoundsof Formula I, or Formula II, or Formula III, or Formula IV, or FormulaV, or Formula VI or a pharmaceutically acceptable salt thereof togetherwith a pharmaceutically acceptable carrier, with other clinicallyrelevant cytotoxic agents or non-cytotoxic agents to a subject in needthereof.

In an embodiment, the present disclosure relates to the use of compoundsof Formula I, or Formula II, or Formula III, or Formula IV, or FormulaV, or Formula VI or a pharmaceutically acceptable salts thereof togetherwith a pharmaceutically acceptable carrier, for the treatment and/orprevention of a proliferative disorder or cancer; or treatment of cancertogether with other clinically relevant cytotoxic agents ornon-cytotoxic agents.

In an embodiment, the present disclosure relates to the use of compoundsof Formula I, or Formula II, or Formula III, or Formula IV, or FormulaV, or Formula VI or pharmaceutically acceptable salts thereof togetherwith a pharmaceutically acceptable carrier, for the treatment and/orprevention of various diseases including proliferative disorder orcancer; or treatment of cancer together with other clinically relevantcytotoxic agents or non-cytotoxic agents, wherein 30 the otherclinically relevant cytotoxic agents or non-cytotoxic agents areselected from the group consisting of carboplatin, bortezomib,carfilzomib, lenalidomide, pomalidomide, doxorubicin, daunorubicin,decitabine, denileukin, denileukin diftitox, dexrazoxane, docetaxel,doxorubicin, dromostanolone propionate cyclophosphamide, 5-fluorouracil,imatinib, methotrexate, irinotecan, toptecan, vinblastine, etoposide,vincristine, carmustine, paclitaxel, vorinostat, belinostat,panbinostat, romidepsin, chiadamide, entinostat, mocetinostat, afatinib,bosutinib, cetuximab, enterctinib, lapatinib, nilotinib, pazopanib,ruxlotinib, sorafenib, sunitinib, vermurafenib, axitinib, gefitinib,cobimetinib, carbozantinib, temozolomide, idarubicin, abarelix,aldesleukin, alemtuzumab, allopurinol, altretamine, anastrozole,asparaginase, bexarotene, baricitinib, bleomycin, busulfan,capecitabine, cladribine, clofarabine, cytarabine, dacarbazine,dactinomycin, sodium, dasatinib, letrozole, tamoxifen, oxaliplatin,procarbazine, zoleronate, and combinations thereof.

In an embodiment, the present disclosure relates to a method for thetreatment of cancer as described herein, wherein said method comprisingadministering a combination of the compounds of Formula I, or FormulaII, or Formula III, or Formula IV, or Formula V, or Formula VI or apharmaceutically acceptable salts thereof together with apharmaceutically acceptable carrier, with other clinically relevantcytotoxic agents or non-cytotoxic agents to a subject in need thereof.

In an aspect of the present disclosure there is provided a method oftreatment and/or prevention of various diseases, including cancer andinfectious diseases, comprising administering to a subject sufferingfrom the viral infectious diseases such as HIV, Influenza, herpes virus,Hepatitis A, Hepatitis B, Hepatitis C, and Hepatitis D, atherapeutically effective amount of the compound of Formula I, FormulaII, Formula III, Formula IV Formula V and Formula VI or thepharmaceutical composition, with other clinically relevant anti-viraldrugs to a subject in need thereof.

In an embodiment, the present disclosure relates to a method oftreatment of cancer as described herein, wherein said method comprisingadministering a combination of the compounds of Formula I, or FormulaII, or Formula III, or Formula IV, or Formula V, or Formula VI or thepharmaceutical composition with other clinically relevant immunemodulators agents to a subject in need of thereof.

EXAMPLES

As used herein the symbols and conventions used in these processes,schemes and examples are consistent with those used in the contemporaryscientific literature, for example, the Journal of the American ChemicalSociety or the Journal of Biological Chemistry. Standard single-letteror three-letter abbreviations are generally used to designate amino acidresidues, which are assumed to be in the L-configuration unlessotherwise noted. Unless otherwise noted, all starting materials wereobtained from commercial suppliers and used without furtherpurification. Specifically, the following abbreviations may be used inthe examples and throughout the specification:

As used herein the symbols and conventions used in these processes,schemes and examples are consistent with those used in the contemporaryscientific literature, for example, the Journal of the American ChemicalSociety or the Journal of Biological Chemistry. Standard single-letteror three-letter abbreviations are generally used to designate amino acidresidues, which are assumed to be in the L-configuration unlessotherwise noted. Unless otherwise noted, all starting materials wereobtained from commercial suppliers and used without furtherpurification. Specifically, the following abbreviations may be used inthe examples and throughout the specification:

Abbreviations Ac Acetyl;

Ac₂O Acetic anhydride;

ACN Acetonitrile; AIBN Azobis(isobutyronitrile);

BINAP 2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl;BMS Borane—dimethyl sulfide complex;

Bn Benzyl; Boc Tert-Butoxycarbonyl;

Boc₂O Di-tert-butyl dicarbonate;

BuLi Butyllithium;

CsF Cesium fluoride;

DCE 1,2-Dichloroethane; DCM Dichloromethane;

DDQ 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone;DMS Dimethyl sufide;ATP Adenosine triphosphate;Bis-pinacolatodiboron4,4,4′,4′,5,5,5′,5′-Octamethyl-2,2′-bi-1,3,2-dioxaborolane;BSA Bovine serum albumin;C18 Refers to 18-carbon alkyl groups on silicon in HPLC stationaryphase;

CH₃CN Acetonitrile; Cy Cyclohexyl;

DIPEA Hünig's base, N-ethyl-N-(1-methylethyl)-2-propanamine;

Dioxane 1,4-Dioxane; DMAP 4Ddimethylaminopyridine; DME1,2-Dimethoxyethane; DMF N,N-Dimethylformamide; DMSO Dimethylsulfoxide;

DPPA Diphenyl phosphoryl azide;EtOAc Ethyl acetate;

EtOH Ethanol;

Et₂O Diethyl ether;HOAc Acetic acid;HPLC High pressure liquid chromatography;

HMDS Hexamethyldisilazide; IPA Isopropylalcohol;

LAH Lithium aluminum hydride;LDA Lithium diisopropylamide;LHMDS Lithium hexamethyldisilazide;

MeOH Methanol;

MPLC Medium pressure liquid chromatography;MTBE Methyl tert-butyl ether;mCPBA m-Chloroperbezoic acid;NaHMDS Sodium hexamethyldisilazide;

NBS N-bromosuccinimide;

NMR Nuclear magnetic resonance;Pd₂(dba)₃ Tris(dibenzylideneacetone)dipalladium(0);

Pd(dppf)Cl₂.DCMComplex[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II).

dichloromethane complex;RPHPLC Reverse phase high pressure liquid chromatography;RT Room temperature;Sat. Saturated;SGC Silica gel chromatography;SM Starting material;TCL Thin layer chromatography;

TEA Triethylamine;

TFA Trifluoroacetic acid; and

THF Tetrahydrofuran.

The following examples provide the details about the synthesis,activities, and applications of the compounds of the present disclosure.It should be understood the following is representative only, and thatthe invention is not limited by the details set forth in these examples.

The compounds of the invention may be made by a variety of methods,including standard chemistry. Any previously defined variable willcontinue to have the previously defined meaning unless otherwiseindicated. Illustrative general synthetic methods are set out in thefollowing schemes and can be readily adapted to prepare other compoundsof the invention.

There is also provided a process as shown in the following scheme1, forthe preparation of compounds of the Formula I, wherein all the groupsare as defined earlier.

General Procedures for the Synthesis of Compounds Disclosed in FormulaI:

Compounds of the invention (VI) were prepared generally according toScheme-1

Compound B was prepared from dimethoxy phenyl propionic acid A, byreacting with polyphosphoric acid. Selective demethylation of compound Bwas performed using BBr₃ to obtain compound C. Upon decarbonylation of Cusing reducing agent compound D was obtained. Formylation of compound Dusing dichloro(methoxy)methane and titanium tetrachloride yieldedcompound E. O-alkylation of E using substituted biphenyl methyl bromidesE1 gave compound F. In some cases of the present invention instead ofbiphenyl methyl bromide E1, biphenyl methyl alcohol E1a was used andfollowed by Mitsunobu reaction conditions to give intermediate F.Reductive amination of intermediate E with various substitutedaliphatic, aromatic, heterocyclic and cyclic amines (E1) resultedcompounds of general formula (VI) of the present invention.Alternatively, R₁ modifications such as O-benzyl substituted compoundsof the general formula VI were prepared by demethylation of E to give5,7-dihydroxy-2,3-dihydro-1H-indene-4-carbaldehyde. Selectivebenzylation of 7-hydroxy using E1 followed by second benzylation of5-hydroxy using E5 or E5a resulted intermediate E6. Reductive aminationof E6 with different amines resulted in compounds of the general formula(VI).

Alternatively, the unsubstituted indane core was prepared according toScheme-2. Decarbonylation of G was performed using trifluoroacetic acidand triethylsilane to obtain intermediate H. Subsequent steps wereperformed following the procedure described in scheme-1 to obtaincompounds of the general formula V and VI.

Alkyl-substituted indane derivatives were prepared according to Scheme3. Formylation of o-cresol gave compound L. By reacting intermediate Lwith acetic anhydride compound M was obtained, which was hydrogenated togive 8-methylchroman-2-one N. Compound N was treated with aluminiumchloride to give indenone derivative O. Decarbonylation of O followed byformylation gave intermediate Q. Subsequent steps were performedfollowing the procedure described in scheme-1 to obtain compounds of thegeneral formula VI.

Biphenyl methyl bromides (E1) or corresponding alcohols were prepared byfollowing Suzuki coupling reaction using corresponding substitutedphenyl boronic acid and substituted bromo benzene.

Halogen-substituted indane derivatives were prepared according toscheme-4. Decarbonylation of 4-hydroxy-2,3-dihydro-1H-inden-1-one Sfollowed by chlorination gave 5-chloro-2,3-dihydro-1H-inden-4-ol U.Intermediate U was formylated to give6-chloro-7-hydroxy-2,3-dihydro-1H-indene-4-carbaldehyde V. Subsequentsteps were performed following the procedure described in Scheme-1 toobtain compounds of the general formula VI.

Ester-substituted indane derivatives were prepared according toscheme-5. O-alkylation of 4-hydroxy-2,3-dihydro-1H-indene-5-carbaldehydegave intermediate Y. Oxidation of aldehyde to acid using sodiumdihydrogen phosphate and hydrogen peroxide gave intermediate Z.Intermediate Z was converted to corresponding ester Z1 using methyliodide in presence of potassium carbonate. Intermediate Z1 was treatedwith TFA and hexamine to give benzyl de-protected aldehyde compoundmethyl 7-formyl-4-hydroxy-2,3-dihydro-1H-indene-5-carboxylate Z2.Subsequent steps were performed following the procedure described inScheme-1 to obtain compounds of the general formula VI.

Compounds of the invention (VI) were prepared also prepared according toScheme-6

Compound E6 was reduced with sodium borohydride to give E7, which wasreacted with pthalimide in presence of TPP and DIAD to obtainintermediate E8. Deprotection of pthalimide group gave free amine of thegeneral formula (VI). Amine of general formula VI was reacted with alkylhalides in presence of base or reductive amination using aldehydes givealkyl amines of the general formula VI. Amides of the general formula VIwere obtained by reaction amine with substituted acids or acidchlorides.

Nitrogen containing bicyclic heterocyclic compounds of the Formula I areprepared according to Scheme-7. Reacting cyclopentanone withmalanonitrile and carbondisulphide gave bicyclic heterocycleintermediate E11. Hydrolysis and decarboxylation was performed usingbase to give E12. Methylation of thiol group using base and methyliodide and O-alkylation using alkyl halide in presence of silveroxide orbase gave intermediate E14. Bromination gave intermediate E15.Sulfoxidation of E15 gave intermediate E16. Nucleophilic displacement ofE6 with E1a resulted with intermediate E17. Bromo to vinyl conversionwas performed by Stille coupling, vinyl group was oxidized to aldehydeto give E19. Reductive amination of E19 with different amines resultedcompounds of the general Formula I.

Some of the intermediates used in present invention were preparedfollowing procedure described in following schemes

Step 1: A stirred solution of 5-bromonicotinonitrile (22 g, 0.120 mol)and tributyl vinyl tin (95.3 g, 0.300 mol) in DMF (200 mL) was purgedwith nitrogen for 10 min. To this mixture, Pd(PPh₃)₄ (13.84 g, 0.012mol) was added and purged again with nitrogen for 20 min. Then themixture was heated at 80° C. for 4 h. After completion, the reactionmixture was diluted with water (200 mL) and extracted with EtOAc (3×200mL). The organic layer was washed with brine, dried over sodium sulfate,filtered and concentrated. The crude was purified by columnchromatography (silica gel, 100-200 mesh) using 10% EtOAc in hexanes toobtain 5-vinylnicotinonitrile as off-white solid (Yield: 10.5 g, 67%).¹H NMR (400 MHz, DMSO-d₆, ppm): δ 5.55 (d, J=10.8 Hz, 1H), 6.17 (d,J=17.6 Hz, 1H), 6.80 (m, 1H), 8.52 (s, 1H), 8.90 (s, 1H), 9.03 (s, 1H).

Step-2: To a stirred solution of 5-vinylnicotinonitrile (10.5 g, 0.081mol) in acetone (200 mL) and water (40 mL) at 0° C., OsO₄ (82 mL, 2.5 wt% solution in tert-butanol, 0.0081 mol) and N-Methylmorpholine N-oxide(29 g, 0.242 mol) were added and stirred for 3 h. To this mixture, NaIO₄(60 g, 0.282 mol) was added and the reaction mixture was allowed to stirat room temperature for 12 h. After completion of the reaction, thereaction mixture was diluted with water (300 mL) and extracted with DCM(2×400 mL). The organic layer was dried over sodium sulfate, filteredand evaporated to give crude product. The crude product was purified oncombiflash chromatography using 30% ethyl acetate in hexane as eluent toafford 5-formylnicotinonitrile (3) as yellow solid (Yield: 7.9 g, 74%).¹H NMR (400 MHz, DMSO-d₆, ppm): δ 8.77 (s, 1H), 9.29 (s, 1H), 9.31 (s,1H), 10.12 (s, 1H).

Step-3: To a stirred solution of 5-formylnicotinonitrile (12 g, 0.091mol) in methanol (100 mL) at 0° C., sodium borohydride (5.12 g, 0.136mol) was added portion wise for 30 minutes and stirred the mixture at 0°C. for 2 h. The reaction mixture was concentrated and the residue wasdiluted with water (100 mL) and DCM (200 mL). The organic layer wasdried over sodium sulfate and concentrated. The crude was purified bycolumn chromatography (silica gel, 100-200 mesh) using 1% MeOH in DCM toobtain 5-(hydroxymethyl)nicotinonitrile as yellow solid (Yield: 7.4 g,60.7%). ¹H NMR (400 MHz, DMSO-d₆, ppm): δ, 8.91 (s, 1H), 8.80 (s, 1H),8.19 (s, 1H), 5.54 (s, 2H), 4.50 (bs, 1H).

Step-4: To a stirred solution of 5-(hydroxymethyl)nicotinonitrile (3 g,0.022 mol) in DCM (30 mL), 4M HCl in 1,4-dioxane (5 mL) was added andconcentrated the mixture under vacuum. To the resulting residue, thionylchloride (20 mL) was added and stirred the mixture at 60° C. for 3 h.After completion, the reaction was cooled to room temperature anddiluted with toluene (150 mL) and filtered off the solid thatprecipitated out. The filtrate was diluted with DCM (200 mL) and washedwith saturated sodium bicarbonate solution (200 mL). The organic layerwas dried over sodium sulphate and concentrated to obtain5-(chloromethyl)nicotinonitrile (Yield: 1.2 g, 35%) as yellow solid. ¹HNMR (400 MHz, DMSO-d₆, ppm): δ 4.86 (s, 2H), 8.42 (s, 1H), 8.94 (d,J=2.0 Hz, 1H), 8.99 (d, J=2.0 Hz, 1H).

Step-1: A solution of 2-amino-3-bromobenzoic acid (10.0 g, 0.046 mol) indry THF (100 mL) at 0° C., borane-DMS (118 mL, 1M in THF, 5 eq) wasadded and stirred the mixture at room temperature for 24 h. Aftercompletion, the reaction was quenched with methanol (20 mL) andconcentrated under vacuum. The residue was diluted with EtOAc (500 mL)and was washed with water (300 mL), saturated sodium bicarbonatesolution (300 mL), brine (200 mL) and concentrated to obtain(2-amino-3-bromophenyl)methanol (Yield: 7.3 g, 78%) as off-white solid.LCMS (ES) m/z=183.96 [M−H₂O+H]⁺ & 185.93 [M+2-H₂O+H]⁺; ¹H NMR (400 MHz,DMSO-d₆, ppm) δ ppm: 4.43 (m, 2H), 5.05 (bs, 2H), 5.21 (m, 1H), 6.50 (t,J=7.6 Hz, 1H), 7.10 (d, J=7.2 Hz, 1H), 7.29 (d, J=7.6 Hz, 1H).

Step-2: A solution of (2-amino-3-bromophenyl)methanol (9.70 g, 0.048mol) and phenyl boronic acid (7.65 g, 0.062 mol) in water (60 mL),toluene (60 mL) and methanol (70 mL) was degassed with nitrogen gas for15 minutes. To this mixture, Pd(PPh₃)₂Cl₂ (3.37 g, 0.0048 mol) andsodium carbonate (13.4 g, 0.127 mol) were added and stirred the mixtureat 80° C. for 8 h. After completion, the mixture was filtered overcelite and washed with EtOAc (2×200 mL). The filtrate was washed withbrine (20 mL) and concentrated. The resulting crude was purified byflash chromatography (silica gel, 12 g cartridge using 0-30% EtOAc inhexanes as eluent to obtain (2-amino-[1,1′-biphenyl]-3-yl)methanol(Yield: 8.2 g, 85%) as off-white solid. LCMS (ES) m/z=200.34 [M+H]⁺; ¹HNMR (400 MHz, DMSO-d₆, ppm) δ: 4.46 (m, 2H), 4.57 (bs, 2H), 5.14 (m,1H), 6.67 (t, J=7.6 Hz, 1H), 6.93 (d, J=7.6 Hz, 1H), 7.05 (d, J=7.2 Hz,1H), 7.34-7.39 (m, 3H), 7.47 (t, J=7.6 Hz, 2H).

Step-3: To a solution of (2-amino-[1,1′-biphenyl]-3-yl)methanol (2.5 g,12.5 mmol) in water (15 mL) and toluene (15 mL), conc.HCl (6 mL) wasadded and cooled the mixture to 0° C. To this mixture, a solution ofsodium nitrite (1.7 g, 18.8 mmol) in water (5 mL) was added slowly andcontinued stirring at 0° C. for 1.5 h. The pH of the solution wasadjusted to 6.0 using sodium carbonate solution. This diazonium solutionwas added slowly to a solution of CuSO₄ (2.3 g, 15 mmol) and sodiumcyanide (3.07 g, 62.5 mmol) in water (15 mL) and toluene (15 mL) at 60°C. After stirring at 60° C. for 2 h, the reaction mixture was cooled toroom temperature and filtered and washed with EtOAc (100 mL). Theorganic layer of the filtrate was washed with brine (20 mL) andconcentrated. The resulting crude was purified by flash chromatography(silica gel, 12 g, cartridge using 0-20% EtOAc in hexanes as eluent toobtain 3-(hydroxymethyl)-[1,1′-biphenyl]-2-carbonitrile (Yield: 450 mg,17%) as brown liquid. LCMS (ES) m/z=210.36 [M+H]⁺; ¹H NMR (400 MHz,DMSO-d₆, ppm) δ: 4.73 (m, 2H), 5.63 (m, 1H), 7.47-7.56 (m, 6H), 7.67 (d,J=8.4 Hz, 1H), 7.77 (t, J=7.6 Hz, 1H).

Step-4: To a stirred solution of3-(hydroxymethyl)-[1,1′-biphenyl]-2-carbonitrile (3.5 g, 16.7 mmol) inDCM (50 mL) at 0° C., triphenyl phosphine (6.5 g, 25.1 mmol) and carbontetrabromide (8.31 g, 25.1 mmol) were added and allowed to stir at roomtemperature for 4 h. After completion, the reaction mixture was dilutedwith water (50 mL) and extracted with DCM (3×200 mL). The organic layerwas dried over sodium sulfate and concentrated. The crude was purifiedby flash chromatography (silica gel, 12 g SNAP) using 0-20% EtOAc inhexanes to obtain 3-(bromomethyl)-[1,1′-biphenyl]-2-carbonitrile (Yield:3.05 g, 66%) as brown solid. ¹H NMR (400 MHz, DMSO-d₆, ppm) δ: 4.87 (s,2H), 7.49-7.59 (m, 6H), 7.75-7.80 (m, 2H).

Step-1: To a stirred solution of methyl 5-fluoronicotinate (9.2 g, 59mmol) in dry THF (40 mL) under nitrogen atmosphere at −78° C., a 2.5 Msolution of LiAlH₄ in THF (31 mL, 77 mmol) was added drop wise andallowed the mixture to stir at same temperature for 40 minutes. Aftercompletion, the reaction was quenched at same temperature with saturatedammonium chloride (10 mL) and poured into ice cold water (100 mL). Themixture was extracted with EtOAc (3×100 mL) and the organic layer wasdried over anhydrous sodium sulphate and concentrated to obtain(5-fluoropyridin-3-yl)methanol (Yield: 7.1 g, 95%) as red coloredliquid. LCMS (ES) m/z=128.30[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm:4.57 (m, 2H), 5.46 (t, J=5.6 Hz, 1H), 7.62 (d, J=10.0 Hz, 1H), 8.41 (s,1H), 8.45 (d, J=2.8 Hz, 1H).

Step-2: To a solution of (5-fluoropyridin-3-yl)methanol (0.5 g, 3.93mmol) in DCM (20 mL) at 0° C., triethylamine (1.63 mL, 11.80 mmol) andp-tosylchloride (2.24 g, 5.90 mmol) were added and then allowed themixture to stir at room temperature for 6 h. The reaction mixture wasdiluted with water (25 mL) and extracted with DCM (3×40 mL). The organiclayer was dried over anhydrous sodium sulphate and concentrated. Thecrude was purified by flash chromatography (silica gel, 12 g cartridge)using 20% EtOAc in hexanes as eluent to obtain3-(chloromethyl)-5-fluoropyridine (Yield: 502 mg, 87%) as off-whitesolid. LCMS (ES) m/z=146.28[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 4.85(s, 2H), 7.85 (d, J=9.2 Hz, 1H), 8.55 (s, 1H), 8.57 (d, J=2.4 Hz, 1H).

Step-1: To a solution of tert-butyl (2-aminoethyl)(methyl)carbamate (4.2g, 25.7 mmol) in ethanol (60 mL), N-hydroxyphthalimide (4.50 g, 25.7mmol) was added and stirred the mixture at 60° C. for 6 h. Aftercompletion, concentrated the mixture under vacuum. The residue waswashed with diethyl ether (2×10 mL) to obtain tert-butyl(2-(1,3-dioxoisoindolin-2-yl)ethyl)(methyl)carbamate (Yield: 5.8 g, 74%)as white solid. LCMS (ES) m/z=305.42 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δppm: 0.97 (s, 6H), 1.09 (s, 3H), 2.77 (s, 3H), 3.43 (m, 2H), 3.72 (t,J=5.2 Hz, 2H), 7.86 (m, 4H).

Step-2: To a solution of tert-butyl(2-(1,3-dioxoisoindolin-2-yl)ethyl)(methyl)carbamate (6 g, 19.7 mmol) in1,4-dioxane (100 mL), 4M HCl in 1,4-dioxane (50 mL) was added andstirred the mixture at room temperature for 3 h. After completion,concentrated the mixture under vacuum. The resulting residue was washedwith diethyl ether (2×10 mL) to obtain HCl salt of2-(2-(methylamino)ethyl)isoindoline-1,3-dione (Yield: 4.0 g, 98%) aswhite solid. LCMS (ES) m/z=205.40 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δppm: 2.56 (s, 3H), 3.18 (m, 2H), 3.89 (t, J=5.6 Hz, 2H), 7.88 (m, 4H),8.83 (bs, 1H). Step-3: To a solution of2-(2-(methylamino)ethyl)isoindoline-1,3-dione (3.5 g, 17.1 mmol) in DMF(40 mL), triethylamine (5.2 g, 51.3 mmol) and acetyl chloride (2 g, 25mmol) were added and stirred for 2 h at room temperature. Aftercompletion, the reaction mixture was diluted with water (50 mL) andextracted with EtOAc (3×100 mL). The organic layer was dried over sodiumsulfate and concentrated. The residue was washed with diethyl ether andpentane to obtainN-(2-(1,3-dioxoisoindolin-2-yl)ethyl)-N-methylacetamide (Yield: 2.5 g,59%) as white solid. LCMS (ES) m/z=247.20 [M+H]⁺.

Step-4: To a solution ofN-(2-(1,3-dioxoisoindolin-2-yl)ethyl)-N-methylacetamide (2.2 g, 8.93mmol) in ethanol (30 mL), hydrazine hydrate (0.58 g, 11.6 mmol) wasadded and stirred the mixture for 6 h at room temperature. Aftercompletion, the mixture was concentrated. The resulting residue wasdiluted with pentane (50 mL) and filtered. Concentration of the filtrateprovided N-(2-aminoethyl)-N-methylacetamide (Yield: 106 mg, 10.2%) as anoil. ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 1.78 (s, 3H), 2.25 (s, 3H), 2.48(m, 2H), 3.09 (m, 2H), 3.22 (m, 2H).

Step-1: To a stirred solution of 3-acetylbenzonitrile (2.0 g, 13.7 mmol)in methanol (30 mL), sodium borohydride (0.62 g, 15.5 mmol) was addedand stirred at room temperature for 6 h. The reaction mixture wasdiluted with water (20 mL) and extracted with EtOAc (3×30 mL). Theorganic layer was dried and concentrated. The resulting crude waspurified by flash chromatography (silica gel, 4 g cartridge) using 20%EtOAc in hexanes to obtain 3-(1-hydroxyethyl)benzonitrile (Yield: 1.8mg, 91%) as colourless liquid. LCMS (ES) m/z=146.05 [M−H]⁺; ¹H NMR (400MHz, DMSO-d₆) δ ppm: 1.32 (d, J=6.4 Hz, 3H), 4.77 (m, 1H), 5.39 (d,J=4.4 Hz, 1H), 7.53 (t, J=7.6 Hz, 1H), 7.69 (d, J=7.6 Hz, 2H), 7.76 (s,1H).

Step-2: To a stirred solution of 3-(1-hydroxyethyl)benzonitrile (1.0 g,6.8 mmol) in DCM (20 mL), carbon tetrabromide (2.67 g, 10 mmol) andtriphenyl phosphine (3.37 g, 10 mmol) were added and stirred the mixtureat room temperature for 4 h. After completion, the reaction mixture wasdiluted with water (10 mL) and separated the layers. The aqueous layerwas further extracted with DCM (2×20 mL) and the combined organic layerwas dried and concentrated. The resulting crude was purified by flashchromatography (silica gel, 4 g cartridge) using 20% EtOAc in hexanes toobtain 3-(1-bromoethyl)benzonitrile (Yield: 600 mg, 42%) as colourlessliquid. LCMS (ES) m/z=146.05 [M−H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm:2.0 (d, J=6.8 Hz, 3H), 5.54 (m, 1H), 7.61 (t, J=7.6 Hz, 1H), 7.79 (d,J=7.6 Hz, 1H), 7.87 (d, J=7.6 Hz, 1H), 8.07 (s, 1H).

Step-1: To a stirred solution of 3-aminopyridine (3.0 g, 31.9 mmol) inTHF (25 mL) at 0° C., acetic anhydride (3.70 g, 38 mmol) was added andstirred the mixture at room temperature for 8 h. After completion, thereaction mixture was diluted with water (25 mL) and extracted with EtOAc(3×50 mL). The combined organic layer was dried over sodium sulphate andconcentrated to obtain N-(pyridin-3-yl)acetamide (Yield: 2.5 g, 58%) aswhite solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 2.07 (s, 3H), 7.32 (m,1H), 8.02 (m, 1H), 8.23 (m, 1H), 8.70 (s, 1H), 10.13 (s, 1H).

Step-2: To a solution of N-(pyridin-3-yl)acetamide (1.5 g, 11.0 mmol),HCl (3 mL) in ethanol (50 mL) was degassed with nitrogen gas for 10 min.To this mixture, PtO₂ (300 mg, 22 mmol) was added and the mixture washydrogenated at 100 Psi pressure for 24 h. After completion, the mixturewas filtered and the filtrate was concentrated under vacuum. Theresulting residue was washed with EtOAc (10 mL) to obtainN-(piperidin-3-yl)acetamide (Yield: 1.0 g, 64%) as off-white solid. LCMS(ES) m/z=143.18 [M+H]⁺.

Step-1: A mixture of 1-bromo-3-fluoro-2-(trifluoromethyl)benzene (15 g,62 mmol), phenyl boronic acid (22.7 g, 186 mmol), 2M sodium carbonate(150 mL), toluene (225 mL) and MeOH (75 mL) was degassed with nitrogengas for 10 minutes. To this mixture, PdCl₂(dppf)DCM complex (5.75 g,8.21 mmol) was added and degassed for another 5 minutes with nitrogen.After sealing the vessel, the mixture was heated at 90° C. for 12 h.After completion, the reaction was diluted with water (300 mL) andextracted with EtOAc (3×300 mL). The organic layer was dried over sodiumsulphate and concentrated. The crude was purified by columnchromatography (silica gel, 100-200 mesh) using 0-1% EtOAc in hexane toobtain 3-fluoro-2-(trifluoromethyl)-1,1′-biphenyl (Yield: 17 g, 39%) ascolourless liquid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 7.21 (d, J=7.6 Hz,1H) 7.31-7.34 (m, 2H), 7.44-7.50 (m, 3H), 7.65 (d, J=7.6 Hz, 1H),7.72-7.78 (m, 1H).

Step-2: To a solution of 3-fluoro-2-(trifluoromethyl)-1,1′-biphenyl(17.0 g, 70.83 mmol) in DMSO (30 mL), KCN (4.6 g, 70.83 mmol) was addedand stirred the mixture at 150° C. for 16 h. After completion, thereaction was diluted with water (100 mL) and extracted with EtOAc (3×100mL). The organic layer was dried over sodium sulphate and concentrated.The crude was purified by column chromatography (silica gel, 100-200mesh) using 0-5% EtOAc in hexanes to obtain2-(trifluoromethyl)-[1,1′-biphenyl]-3-carbonitrile (Yield: 10.0 g, 58%)as yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 7.31-7.34 (m, 2H),7.44-7.50 (m, 3H), 7.74 (d, J=6.4 Hz, 1H), 7.91 (t, J=8.0 Hz, 1H), 8.19(d, J=7.6 Hz, 1H).

Step-3: To a solution of2-(trifluoromethyl)-[1,1′-biphenyl]-3-carbonitrile (1.0 g, 4.0 mmol) indry DCM (5 mL) at −65° C., DIBAl-H (1M solution in hexanes, 6.0 mL, 6.0mmol) was added drop wise and stirred the mixture at −65° C. for 1 h.After completion, the reaction was quenched with cold water (20 mL) andextracted with DCM (3×25 mL). The organic layer was dried over sodiumsulphate and concentrated. The crude was purified by flashchromatography (silica gel, 12 g cartridge) using 0-10% EtOAc in hexanesto obtain 2-(trifluoromethyl)-[1,1′-biphenyl]-3-carbaldehyde (Yield: 0.4g, 39.5%) as colourless liquid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 7.35(m, 2H), 7.47 (m, 3H), 7.67 (d, J=6.4 Hz, 1H), 7.89 (t, J=8.0 Hz, 1H),7.99 (d, J=7.6 Hz, 1H), 10.37 (s, 1H).

Step-4: To a solution of2-(trifluoromethyl)-[1,1′-biphenyl]-3-carbaldehyde (3.0 g, 12 mmol) inEtOH (30 mL) and THF (10 mL) at 0° C., sodium borohydride (0.90 g, 24mmol) was added and allowed to stir at room temperature for 2 h. Aftercompletion of reaction, the reaction was quenched with water (50 mL) andextracted with EtOAc (3×100 mL). The organic layer was dried over sodiumsulphate and concentrated to obtain(2-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)methanol (Yield: 2.70 g, 90%)as yellow sticky liquid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 4.73 (s, 2H),5.53 (m, 1H), 7.21 (d, J=7.6 Hz, 1H), 7.25 (d, J=6.8 Hz, 2H), 7.38-7.43(m, 3H), 7.66 (t, J=8.0 Hz, 1H), 7.83 (d, J=7.6 Hz, 1H).

Step-5: To a solution of(2-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)methanol (0.1 g, 0.39 mmol) inDCM (10 mL) at 0° C., triphenyl phosphine (0.25 g, 0.99 mmol) and carbontetrabromide (0.33 g, 0.99 mmol) were added and allowed the mixture tostir at room temperature for 8 h. After completion of reaction, thereaction was diluted with water (10 mL) and extracted with DCM (3×20mL). The organic layer was dried over sodium sulphate and concentratedto obtain 3-(bromomethyl)-2-(trifluoromethyl)-1,1′-biphenyl (Yield: 100mg, 80%) as off-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 4.87 (s,1H), 4.95 (s, 1H), 7.26-7.28 (m, 2H), 7.30-7.36 (m, 1H), 7.42 (m, 3H),7.68-7.76 (m, 2H).

Step-1: To a stirred solution of dimethyl(1R,2S)-cyclopropane-1,2-dicarboxylate (2.0 g, 12.6 mmol) in THF (40mL), a solution of lithium hydroxide monohydrate (0.53 g, 12.6 mmol) inwater (40 mL) was added slowly and stirred for about 1 h. The reactionwas cooled to 0° C. and pH was adjusted to 5-6. The aqueous mixture wasextracted with 5% MeOH in DCM (3×50 mL) and the combined organic layerwas dried over sodium sulphate and concentrated to obtain(1S,2R)-2-(methoxycarbonyl)cyclopropane-1-carboxylic acid (Yield: 0.80g, 44%) as colourless liquid. LCMS (ES) m/z=143 [M−H]⁺; ¹H NMR (400 MHz,DMSO-d₆) δ ppm: 1.17 (m, 1H), 1.32 (m, 1H), 1.99-2.03 (m, 1H), 2.10-2.16(m, 1H), 3.56 (s, 3H), 12.33 (s, 1H).

Step-2: To a solution of(1S,2R)-2-(methoxycarbonyl)cyclopropane-1-carboxylic acid (0.80 g, 5.5mmol) in THF (15 mL) under nitrogen atmosphere at 0° C., borane-DMS(0.84 g, 11.1 mmol) was added and allowed the reaction mixture to stirat room temperature for 6 h. After completion, the reaction was quenchedwith MeOH (10 mL) at 0° C. and concentrated under vacuum. The resultingcrude was purified by flash chromatography (silica gel, 4 g cartridge)using 5% MeOH in DCM as eluent to obtain methyl(1R,2S)-2-(hydroxymethyl)cyclopropane-1-carboxylate (Yield: 0.550 g,76%) as colourless liquid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 0.82 (m,1H), 1.05 (m, 1H), 1.50 (m, 1H), 1.72 (m, 1H), 3.38 (m, 1H), 3.58 (s,3H), 3.62 (m, 1H), 4.51 (m, 1H).

Step-3: To a stirred solution of methyl(1R,2S)-2-(hydroxymethyl)cyclopropane-1-carboxylate (0.25 g, 1.9 mmol)in DCM (5 mL), triethylamine (0.58 g, 5.7 mmol), and DMAP (23 mg, 0.19mmol) were added and stirred for 10 minutes. To this mixture, tosylchloride (0.55 g, 2.8 mmol) was added and allowed the mixture to stir atroom temperature for 6 h. After completion, the reaction mixture wasdiluted with water (10 mL) and extracted with DCM (3×15 mL). The organiclayer was dried over sodium sulphate and concentrated. The resultingcrude was purified by flash chromatography (silica gel, 4 g cartridge)using 5% MeOH in DCM as eluent to obtain methyl(1R,2S)-2-((tosyloxy)methyl)cyclopropane-1-carboxylate (Yield: 0.330 g,60%) as colourless liquid.

The following examples illustrate the invention. These examples are notintended to limit the scope of the present invention, but rather toprovide guidance to the skilled artisan to prepare and use thecompounds, compositions, and methods of the present invention. Whileparticular embodiments of the present invention are described, theskilled artisan will appreciate that various changes and modificationscan be made without departing from the spirit and scope of theinvention.

TABLE 1 Prep-HPLC methods: Compounds purified by prep Method ColumnMobile phase HPLC A Xbridge Shield C-18, 19 × 5 Mm Ammonium 32, 12, 86250 mm, 10 u Acetate in water: Acetonitrile B Xselect CSH phenyl 5 MmAmmonium 46, 49, 85, hexyl, 19 × 250 mm, 5 u Acetate in water: 56, 93,94 Acetonitrile C Xselect CSH phenyl 0.1% TFA in water: 47 hexyl, 19 ×250 mm, 5 u Acetonitrile D Sunfire C18, 19 × 250 5 mM Ammonium 76, 52,81 mm, 10μ Acetate in water: Acetonitrile. E Sunfire C18, 19 × 250 0.1%Formic Acid in 79 mm, 10μ water:Acetonitrile. F XTERRA C18, 19 × 250 5mM Ammonium 63 mm, 10μ Bicarbonate in water: Acetonitrile

Example 1(S)-1-((7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylic acid (1)

Step 1: To a solution of 4-hydroxy-2,3-dihydro-1H-inden-1-one (2.0 g,13.5 mmol) in TFA (20 mL) at room temperature was added triethylsilane(5.3 mL, 33.72 mmol). The mixture was stirred at 100° C. for 16 h. Thereaction mixture was cooled to room temperature and concentrated. Theresidue was quenched with sodium bicarbonate solution, extracted intoethyl acetate. The organic layer was dried over sodium sulphate andevaporated to obtain crude product, which was purified on combiflashMPLC using 10% EtOAc in Hexane as eluent to afford2,3-dihydro-1H-inden-4-ol (1.8 g, crude) as pale brown liquid. ¹H NMR(400 MHz, DMSO-d₆) δ ppm: 1.90-1.96 (m, 2H), 2.71 (t, J=7.4 Hz, 2H),2.79 (t, J=7.6 Hz, 2H), 6.52 (d, J=8.0 Hz, 1H), 6.64 (d, J=7.6 Hz, 1H),6.89 (t, J=7.8 Hz, 1H), 9.04 (s, 1H).

Step 2: To a mixture of 2,3-dihydro-1H-inden-4-ol (1.8 g, 13.43 mmol) inDCM (20 mL) was added TiCl₄ (2.7 mL, 24.17 mmol) at 0° C. and thereaction mixture was stirred for 15 min. Dichloro(methoxy)methane (1.3mL, 14.77 mmol) was added to the reaction mixture at 0° C. The mixturewas stirred at room temperature for 2 h. The reaction mixture wasquenched with cold water and extracted with DCM. The combined organiclayer was dried over sodium sulphate and evaporated to obtain crudewhich was purified on combiflash MPLC using 20% EtOAc in Hexane aseluent to afford 7-hydroxy-2,3-dihydro-1H-indene-4-carbaldehyde (0.31 g,crude) as white solid. LCMS (ES) m/z=163.1 [M+H.]⁺. ¹H NMR (400 MHz,DMSO-d₆) δ ppm: 2.00-2.04 (m, 2H), 2.73 (t, J=7.4 Hz, 2H), 3.16 (t,J=7.4 Hz, 2H), 6.75 (d, J=8.0 Hz, 1H), 7.52 (d, J=8.0 Hz, 1H), 9.86 (s,1H), 10.34 (s, 1H).

Step 3: To a mixture of 7-hydroxy-2,3-dihydro-1H-indene-4-carbaldehyde(0.31 g, 1.91 mmol, 1 equiv) in ACN (10 mL) was added potassiumcarbonate (0.39 g, 2.87 mmol, 1.5 equiv). The reaction mixture wasstirred at room temperature for 15 min.3-(bromomethyl)-2-methyl-1,1′-biphenyl (0.5 g, 1.91 mmol, 1.0 equiv) wasadded to the reaction mixture and stirred at room temperature for 2 h.The reaction mixture was quenched with water and extracted with DCM. Thecombined organic layer was dried over sodium sulphate and evaporated toobtain crude product, which was purified on combiflash MPLC using 10%EtOAc in Hexane as eluent to afford7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-indene-4-carbaldehyde(0.6 g, 92%) as white solid. LCMS (ES) m/z=343.2 [M+H.]⁺. ¹H NMR (400MHz, DMSO-d₆) δ ppm: 2.02-2.09 (m, 2H), 2.19 (s, 3H), 2.81 (t, J=7.4 Hz,2H), 3.20 (t, J=7.6 Hz, 2H), 5.28 (s, 2H), 7.18 (t, J=9.0 Hz, 2H),7.25-7.31 (m, 3H), 7.34-7.38 (m, 1H), 7.42-7.46 (m, 3H), 7.72 (d, J=8.4Hz, 1H), 9.95 (s, 1H).

Step 4: To a mixture of7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-indene-4-carbaldehyde(0.1 g, 0.29 mmol) and (S)-piperidine-2-carboxylic acid (0.045 g, 0.35mmol) in DMF:MeOH (10 mL) was added one drop of acetic acid at roomtemperature and the reaction mixture was stirred for 15 min. Sodiumcyanoborohydride (0.054 g, 0.87 mmol) was added to the reaction mixtureand the mixture was stirred at room temperature for 16 h. The reactionmixture was quenched with water and extracted with DCM. The combinedorganic layer was washed with sodium bicarbonate solution and dried oversodium sulphate and evaporated to obtain crude product, which waspurified on combiflash MPLC using 20% MeOH in DCM as eluent to afford(S)-1-((7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylicacid (15 mg, 11%) as white solid. LCMS (ES) m/z=456.2 [M+H. ¹H NMR (400MHz, DMSO-d₆) δ ppm: 1.35-1.46 (m, 3H), 1.71-1.73 (m, 2H), 1.95-1.99 (m,2H), 2.18-2.25 (m, 4H), 2.78-3.05 (m, 6H), 3.41-3.71 (m, 2H), 3.81-4.45(m, 2H), 5.12 (s, 2H), 6.87 (d, J=8.0 Hz, 1H), 7.08 (d, J=8.0 Hz, 1H),7.17 (d, J=7.6 Hz, 1H), 7.24-7.31 (m, 3H), 7.34-7.37 (m, 1H), 7.42-7.45(m, 3H).

Example 2N-(2-(((5-methoxy-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)amino)ethyl)acetamide (2)

Step 1: A solution of 3-(3,5-dimethoxyphenyl)propanoic acid (10.0 g,147.61 mmol) in polyphosphoric acid (100 mL) was stirred for 16 h at 80°C. The reaction mixture was cooled to room temperature and quenched withwater, extracted using ethyl acetate. The organic layer was dried oversodium sulphate and evaporated to obtain crude product, which waspurified on combiflash MPLC using 20% EtOAc in hexane as eluent toafford 5,7-dimethoxy-2,3-dihydro-1H-inden-1-one (4.0 g, 43%) as palebrown solid. LCMS (ES) m/z=193.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δppm: 2.63-2.69 (m, 2H), 3.00-3.03 (m, 2H), 3.86 (s, 3H), 3.90 (s, 3H),6.29 (s, 1H), 6.48 (s, 1H).

Step 2: To a solution of 5,7-dimethoxy-2,3-dihydro-1H-inden-1-one (3.5g, 18.22 mmol) in DCM (50 mL) was added BBr₃ (1.71 mL, 17.18 mmol) dropwise over a period of 5 min at 0° C. and the reaction mixture wasstirred at room temperature for 1 h. The reaction mixture was quenchedwith ice water and extracted with DCM. The organic layer was dried oversodium sulphate and evaporated to obtain crude which was purified oncombiflash MPLC using 20% EtOAc in hexane as eluent to afford7-hydroxy-5-methoxy-2,3-dihydro-1H-inden-1-one (3.5 g, crude) as palebrown solid. LCMS (ES) m/z=179.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δppm: 2.48-2.52 (m, 2H), 2.92-2.95 (m, 2H), 3.77 (s, 3H), 6.24 (s, 1H),6.51 (s, 1H), 9.85 (s, 1H).

Step 3: To a mixture of sodium borohydride (2.24 g, 58.98 mmol) in THF(50 mL) was added BF₃.Et₂O (24.2 mL, 196.66 mmol) drop wise over aperiod of 10 min at 0° C. After stirring at 0° C. for 1 h,7-hydroxy-5-methoxy-2,3-dihydro-1H-inden-1-one (3.5 g, 19.66 mmol) inTHF (20 mL) was added to the reaction mixture which was further stirredat room temperature for 16 h. The reaction mixture was quenched with icewater, extracted with DCM. The organic layer was dried over sodiumsulphate and evaporated to obtain crude product, which was purified oncombiflash MPLC using 20% EtOAc in hexane as eluent to afford6-methoxy-2,3-dihydro-1H-inden-4-ol (2.5 g, crude) as pale brown solid.¹H NMR (400 MHz, DMSO-d₆) δ ppm: 1.89-1.96 (m, 2H), 2.61-2.65 (m, 2H),2.72-2.76 (m, 2H), 3.62 (s, 3H), 6.12 (s, 1H), 6.25 (s, 1H), 9.08 (s,1H).

Step 4: To a solution of 6-methoxy-2,3-dihydro-1H-inden-4-ol (2.5 g,15.24 mmol) in DCM (50 mL) was added TiCl₄ (3.0 mL, 27.13 mmol) at 0° C.and stirred for 15 min. Dichloro(methoxy)methane (1.5 mL, 16.76 mmol)was added to the reaction mixture at 0° C. and stirred for additional 2h at room temperature. The reaction mixture was quenched with cold waterand extracted with DCM. The combined organic layer was dried over sodiumsulphate and evaporated to obtain crude product, which was purified oncombiflash MPLC using 20% EtOAc in hexane as eluent to afford7-hydroxy-5-methoxy-2,3-dihydro-1H-indene-4-carbaldehyde (0.1 g, crude)as white solid. LCMS (ES) m/z=193.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δppm: 1.91-1.97 (m, 2H), 2.60-2.64 (m, 2H), 3.04-3.08 (m, 2H), 3.78 (s,3H), 6.34 (s, 1H), 10.22 (s, 1H), 10.41 (s, 1H).

Step 5: To a solution of7-hydroxy-5-methoxy-2,3-dihydro-1H-indene-4-carbaldehyde (0.1 g, 0.52mmol) in ACN (15 mL) was added potassium carbonate (0.10 g, 0.78 mmol)at room temperature. The mixture was stirred for 15 min and3-(bromomethyl)-2-methyl-1,1′-biphenyl (0.13 g, 0.52 mmol) was added tothe reaction mixture at room temperature. The reaction mixture wasfurther stirred for 5 h. The reaction mixture was quenched with waterand extracted with DCM. The combined organic layer was dried over sodiumsulphate and evaporated to obtain crude product, which was purified oncombiflash MPLC using 10% EtOAc in Hexane as eluent to afford5-methoxy-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-indene-4-carbaldehyde(0.1 g, crude) as white solid. LCMS (ES) m/z=373.2 [M+H]⁺. ¹H NMR (400MHz, DMSO-d₆) δ ppm: 1.96-2.00 (m, 2H), 2.21 (s, 3H), 2.65-2.70 (m, 2H),3.08-3.11 (m, 2H), 3.92 (s, 3H), 5.31 (s, 2H), 6.78 (s, 1H), 7.19-7.21(m, 1H), 7.27-7.38 (m, 4H), 7.42-7.50 (m, 3H), 10.29 (s, 1H).

Step 6: To a mixture of5-methoxy-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-indene-4-carbaldehyde(0.05 g, 0.13 mmol) and N-(2-aminoethyl)acetamide (0.02 g, 0.20 mmol) inDMF:MeOH (10 mL) was added one drop acetic acid at room temperature. Themixture was stirred for 15 min and sodium cyanoborohydride (0.025 g,0.40 mmol) was added to the reaction mixture. The reaction mixture wasfurther allowed to stir at room temperature for 16 h. The reactionmixture was quenched with water and extracted with DCM. The combinedorganic layer was washed with sodium bicarbonate solution and dried oversodium sulphate and evaporated to obtain crude which was purified oncombiflash MPLC using 20% MeOH in DCM as eluent to affordN-(2-(((5-methoxy-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)amino)ethyl)acetamide(10 mg, 16%) as white solid. LCMS (ES) m/z=459.2 [M+H.]⁺. HPLC purity98.29%. ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 1.22 (bs, 2H), 1.75 (s, 3H),1.94-1.97 (s, 2H), 2.20 (s, 3H), 2.71-2.75 (m, 2H), 2.82-2.86 (s, 2H),3.08-3.09 (s, 2H), 3.57 (s, 2H), 3.77 (s, 3H), 5.15 (s, 2H), 6.61 (s,1H), 7.16-7.38 (m, 5H), 7.42-7.47 (m, 3H), 7.73 (bs, 1H).

Example 3(S)-1-((7-((3-(1-(3-(3,3-difluoropyrrolidin-1-yl)propyl)-1H-indol-4-yl)-2-methylbenzyl)oxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylicacid (3)

Step 1: To a solution of 5-bromo indole (1 g, 5.1 mmol) in DMF (60 mL)was added NaH (0.22 g, 5.6 mmol) at 0° C. The reaction mixture wasstirred at room temperature for 30 min. Then 1-bromo-3-chloropropane(0.88 g, 5.6 mmol) was added to the reaction mixture at 0° C. and thereaction was stirred at room temperature for 6 h. The reaction mixturewas quenched with water and extracted into ethyl acetate (2×100 mL). Thecombined organic layers were washed with brine, dried over sodiumsulphate and evaporated to give the crude residue which was purified oncombiflash MPLC using 9% ethyl acetate in Hexane to afford4-bromo-1-(3-chloropropyl)-1H-indole as yellow viscous liquid (1.2 g,86%). LCMS (ES) m/z=272.0 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 2.18(t, J=5.4 Hz, 2H), 3.53 (t, J=6.0 Hz, 2H), 4.31 (t, J=6.8 Hz, 2H)), 6.40(bs, 1H), 7.07 (t, J=8.0 Hz, 1H), 7.23 (d, t, J=7.6 Hz, 1H), 7.49-7.54(m, 2H).

Step 2: To a stirred solution of 4-bromo-1-(3-chloropropyl)-1H-indole(0.9 g, 3.3 mmol) and(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol(0.98 g, 3.97 mmol) in dioxane:water (20 mL: 4 mL) were added Xphos (0.3g, 0.33 mmol), CsF (1 g, 6.6 mmol), and Pd₂(dba)₃ (0.27 g, 0.33 mmol)simultaneously and the reaction mixture was purged with nitrogen for 15min. The reaction mixture was then heated at 85° C. for 14 h in a sealedtube. The reaction mixture was filtered over celite, the filtrate wasdiluted with water and extracted into ethyl acetate (2×50 mL). Thecombined organic layers were washed with brine, dried over sodiumsulphate and evaporated to get the crude residue which was purified oncombiflash MPLC using 10% ethyl acetate in hexane to afford(3-(1-(3-chloropropyl)-1H-indol-4-yl)-2-methylphenyl)methanol as brownviscous liquid (0.8 g, 96%). LCMS (ES) m/z=314.1 [M+H]. ¹H NMR (400 MHz,DMSO-d₆) δ ppm: 1.13-1.22 (m, 4H), 1.99 (s, 3H), 2.19-2.24 (m, 2H), 3.58(t, J=6 Hz, 2H), 4.32 (bs, 2H), 4.54-4.55 (m, 2H), 5.07 (bs, 1H), 6.00(s, 1H), 6.84 (d, J=7.2 Hz, 1H), 7.11 (d, J=7.6 Hz, 1H), 7.20 (q, J=8Hz, 2H), 7.33-7.34 (m, 1H), 7.40 (d, J=7.6 Hz, 1H), 7.47 (d, J=8.4 Hz,1H).

Step 3: To a solution of(3-(1-(3-chloropropyl)-1H-indol-4-yl)-2-methylphenyl)methanol (0.2 g,0.6 mmol) in DMF (10 mL) were added 3,3-difluoropyrrolidinehydrochloride (0.133 g, 0.95 mmol), sodium iodide (0.143 g, 0.95 mmol)and K₂CO₃ (0.172 g, 1.27 mmol) simultaneously and the reaction mixturewas heated at 80° C. for 16 h. The reaction mixture was cooled to roomtemperature, diluted with ice cooled water and extracted with ethylacetate (2×50 mL). The combined organic layers were washed with brine,dried over sodium sulphate and evaporated to give the crude residuewhich was purified on combiflash MPLC using 15% ethyl acetate in hexaneto afford(3-(1-(3-(3,3-difluoropyrrolidin-1-yl)propyl)-1H-indol-4-yl)-2-methylphenyl)methanolas brown viscous liquid (0.13 g, 43%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm:1.90-1.97 (m, 2H), 2.00 (s, 3H), 2.12-2.18 (m, 2H), 2.37-2.48 (m, 2H),2.62-2.64 (m, 2H), 2.81-2.87 (m, 2H), 4.18-4.25 (bs, 2H), 451-4.52 (m,2H), 5.12-5.20 (m, 1H), 5.97 (s, 1H), 6.83 (d, J=7.2 Hz, 1H), 7.11 (d,J=7.6 Hz, 1H), 7.16-7.23 (m, 2H), 7.32 (bs, 1H), 7.39 (d, J=7.6 Hz, 2H),7.45 (d, J=8.4 Hz, 1H).

Step 4: To a stirred solution(3-(1-(3-(3,3-difluoropyrrolidin-1-yl)propyl)-1H-indol-4-yl)-2-methylphenyl)methanol(0.3 g, 0.78 mmol) in DCM (20 mL) was added PBr₃ (0.42 g, 1.56 mmol)drop wise at 0° C. and the reaction mixture was stirred for 3 h at roomtemperature. The reaction mixture was quenched with a saturated sodiumbicarbonate solution and extracted with ethyl acetate (2×50 mL). Thecombined organic layer was washed with brine, dried over sodium sulphateand evaporated to afford4-(3-(bromomethyl)-2-methylphenyl)-1-(3-(3,3-difluoropyrrolidin-1-yl)propyl)-1H-indoleas colorless viscous liquid (0.2 g, 59%). LCMS (ES) m/z=447, 449 [M,M+2H]⁺.

Step 5: To a stirred solution of7-hydroxy-2,3-dihydro-1H-indene-4-carbaldehyde (0.05 g, 0.13 mmol) and4-(3-(bromomethyl)-2-methylphenyl)-1-(3-(3,3-difluoropyrrolidin-1-yl)propyl)-1H-indole(0.2, 0.34 mmol) in ACN (10 mL) was added K₂CO₃ (0.07 g, 0.41 mmol) andthe reaction mixture was stirred for 14 h at room temperature. Thereaction mixture was quenched with water, extracted into ethyl acetate(2×50 mL). The combined organic layer was washed with brine, dried oversodium sulphate and evaporated. The crude was purified on combiflashMPLC using 20%-ethyl acetate in hexane as eluent to afford7-((3-(1-(3-(3,3-difluoropyrrolidin-1-yl)propyl)-1H-indol-4-yl)-2-methylbenzyl)oxy)-2,3-dihydro-1H-indene-4-carbaldehydeas colorless viscous oil (0.09 g, 36%). LCMS (ES) m/z=529.3, [M+H]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ ppm: 1.14-1.18 (m, 3H), 1.91-1.94 (m, 2H), 1.97(s, 2H), 2.05-2.10 (m, 5H), 2.19-2.26 (m, 2H), 2.81-2.88 (m, 4H), 4.23(bs, 2H), 5.31 (s, 2H), 5.99 (s, 1H), 6.88 (d, J=7.2 Hz, 1H), 7.16-7.28(m, 4H), 7.35-7.36 (m, 1H), 7.47 (d, J=8.0 Hz, 2H), 7.72-7.25 (m, 1H),9.95 (s, 1H).

Step 6: To a solution of7-((3-(1-(3-(3,3-difluoropyrrolidin-1-yl)propyl)-1H-indol-4-yl)-2-methylbenzyl)oxy)-2,3-dihydro-1H-indene-4-carbaldehyde(0.05 g, 0.09 mmol) in MeOH (2 mL) and DMF (2 mL) were added(S)-piperidine-2-carboxylic acid (0.037 g, 0.28 mmol) and acetic acid(0.05 mL) simultaneously and the reaction mixture was stirred at 50° C.for 2 h. The reaction mixture was then cooled to 0° C., NaCNBH₃ (0.030g, 0.283 mmol) was added and the reaction mixture was stirred at r.t for16 h. The reaction mixture was evaporated; the crude was taken in DCM(15 mL) and washed with water and brine. The organic layer was driedover sodium sulphate, concentrated to get the crude residue which waspurified on combiflash MPLC using 5% methanol in dichloromethane aseluent to afford1-((4-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-5,6,7,8-tetrahydronaphthalen-1-yl)methyl)piperidine-2-carboxylicacid as white crystalline solid (0.006 g, 10%). LCMS (ES) m/z=642.3[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 1.35-1.55 (m, 5H), 1.72 (bs,2H), 1.92-1.99 (m, 5H), 2.09 (s, 3H), 2.21-2.26 (m, 3H), 2.31-2.37 (m,4H), 2.81-2.91 (m, 7H), 3.81-3.84 (m, 1H), 4.22 (bs, 2H), 5.14 (s, 2H),5.99 (s, 1H), 6.87 (d, J=7.2 Hz, 2H), 7.08 (d, J=7.6 Hz, 1H), 7.20-7.28(m, 3H), 7.35 (s, 1H), 7.45-7.48 (m, 2H).

Example 4(S)-1-((6-methyl-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylicacid (4)

Step-1: To a solution of o-cresol (4.0 g, 0.0369 mol) in acetonitrile(100 mL), magnesium chloride (5.2 g, 0.055 mol) and triethylamine (9.35g, 0.092 mol) were added and the mixture was stirred for 15 minutes.Paraformaldehyde (5.5 g, 0.185 mol) was added and the mixture was heatedat 90° C. for 3 h. After completion of the reaction, the reactionmixture was concentrated under reduced pressure and the residue wasdiluted with aqueous 1N HCl solution (100 mL). The aqueous mixture wasextracted with EtOAc (2×100 mL) and the organic layer was washed withbrine (50 mL), dried over sodium sulfate and concentrated. The resultingcrude was purified by flash chromatography (silica gel, 12 g) using 4%EtOAc in hexane as eluent to afford 2-hydroxy-3-methylbenzaldehyde(Yield: 1.7 g, 34%) as light greenish solid. ¹H NMR (400 MHz, CDCl₃) δppm: 2.28 (s, 3H), 6.93 (t, J=7.6 Hz, 1H), 7.39 (d, J=7.6 Hz, 2H), 9.88(s, 1H), 11.27 (s, 1H).

Step-2: To a solution of 2-hydroxy-3-methylbenzaldehyde (10 g, 70 mmol)in acetic anhydride (15 g, 146 mmol), sodium acetate (15 g, 183 mmol)was added. The mixture was heated at 180° C. for 10 h. After completionof reaction, the mixture was cooled and diluted with water (300 mL). Themixture was extracted with EtOAc (3×500 mL) and the combined extractswere washed with saturated sodium bicarbonate solution (250 mL), water(100 mL), brine (100 mL), dried over sodium sulfate and concentratedunder reduced pressure. The resulting crude mixture was purified byflash chromatography (silica gel, 40 g) using 15% EtOAc in hexane aseluent to give 8-methyl-2H-chromen-2-one (Yield: 4.1 g, 35%) asoff-white solid. ¹H NMR (400 MHz, CDCl₃) δ ppm: 2.46 (s, 3H), 6.41 (t,J=9.6 Hz, 1H), 7.18 (t, J=7.6 Hz, 1H), 7.32 (d, J=7.6 Hz, 1H), 7.38 (d,J=7.2 Hz, 1H), 7.70 (d, J=9.6 Hz, 1H).

Step-3: To a solution of 8-methyl-2H-chromen-2-one (8.0 g, 50 mmol) inAcOH (60 mL), 10% palladium on carbon (50% wet, 4.0 g) was added undernitrogen and the resulting mixture was hydrogenated using a hydrogenballoon for 4 h at room temperature. After completion of reaction, thereaction mixture was filtered over celite bed and the bed was washedwith EtOAc (20 mL). The filtrate was washed with saturated sodiumbicarbonate solution (10 mL), water (10 mL), brine (10 mL), dried oversodium sulfate and concentrated under vacuum to obtain8-methylchroman-2-one (3.40 g, crude). ¹H NMR (400 MHz, CDCl₃) δ ppm:2.30 (s, 3H), 2.77 (m, 2H), 2.98 (m, 2H), 6.97-7.02 (m, 2H), 7.10 (d,J=6.0 Hz, 1H).

Step-4: A mixture of 8-methylchroman-2-one (2.0 g, 13.5 mmol) andanhydrous AlCl₃ (5.4 g, 40.5 mmol) was heated at 180° C. for 2 h. Aftercompletion of the reaction, it was cooled and quenched with ice coldwater (100 mL). The aqueous mixture was extracted with EtOAc (3×100 mL)and the EtOAc extract was dried over sodium sulfate and concentrated.The resulting residue was triturated with pentane and filtered to obtain4-hydroxy-5-methyl-2,3-dihydro-1H-inden-1-one (Yield: 1.7 g, 67%) asbrown solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 2.24 (s, 3H), 2.59 (m,2H), 2.95 (m, 2H), 7.04 (d, J=7.6 Hz, 1H), 7.15 (d, J=7.6 Hz, 1H), 9.19(s, 1H).

Step-5: To a solution of 4-hydroxy-5-methyl-2,3-dihydro-1H-inden-1-one(0.70 g, 4.3 mmol) in 1,2-dichloroethane (20 mL) at room temperatureunder nitrogen atmosphere, sodium cyanoborohydride (0.8 g, 12.9 mmol)and ZnI₂ (5.5 g, 17 mmol) were added slowly and the resulting mixturewas heated at 80° C. for 16 h. After completion, the reaction mixturewas quenched with water (50 mL) and filtered through celite bed. The bedwas washed with EtOAc (200 mL) and the filtrate was dried over sodiumsulfate and concentrated under vacuum. The resulting crude was purifiedby column chromatography (silica gel, 100-200 mesh) using 20% EtOAc inhexane to afford 5-methyl-2,3-dihydro-1H-inden-4-ol (Yield: 0.50 g, 72%)as white solid. ¹H NMR (400 MHz, CDCl₃) δ ppm: 2.10 (m, 2H), 2.23 (s,3H), 2.82 (m, 2H), 2.90 (m, 2H), 6.73 (d, J=7.2 Hz, 1H), 6.92 (d, J=7.2Hz, 1H).

Step-6: To a solution of 5-methyl-2,3-dihydro-1H-inden-4-ol (0.50 g, 3.3mmol) in TFA (12.5 mL), hexamine (0.56 g, 4.0 mmol) was added and themixture was stirred at 120° C. for 3 h. After cooling the mixture to 0°C., a 10% aqueous H₂SO₄ solution (12.5 mL) was added and the mixture washeated at 100° C. for 2 h. The reaction mixture was cooled to roomtemperature and quenched with solid sodium bicarbonate until theeffervescence stopped. After diluting the mixture with water (50 mL), itwas extracted with DCM (3×50 mL) and the organic extract was dried oversodium sulfate and concentrated. The resulting crude was purified byflash chromatography (silica gel, 4 g) using 20% EtOAc in hexane toobtain 7-hydroxy-6-methyl-2,3-dihydro-1H-indene-4-carbaldehyde (Yield:220 mg, 38%) as yellow solid. LCMS (ES) m/z=177.24 [M+H]⁺; ¹H NMR (400MHz, DMSO-d₆) δ ppm: 2.18 (m, 2H), 2.29 (s, 3H), 2.82 (t, J=7.2 Hz, 2H),3.29 (t, J=7.2 Hz, 2H), 5.05 (m, 1H), 7.46 (s, 1H), 9.97 (s, 1H).

Step-7: To a solution of7-hydroxy-6-methyl-2,3-dihydro-1H-indene-4-carbaldehyde (0.22 g, 1.25mmol) in acetonitrile (5 mL), potassium carbonate (0.25 g, 1.86 mmol)was added and the reaction mixture was stirred for 30 min.3-(bromomethyl)-2-methyl-1,1′-biphenyl (0.32 g, 1.25 mmol) was added andthe reaction mixture was stirred for 5 h. After completion, the reactionmixture was diluted with water (10 mL) and extracted with EtOAc (3×10mL). The combined organic layer was dried over sodium sulfate andconcentrated. The resulting crude was purified by flash chromatography(silica gel, 4 g) using 0-20% EtOAc in hexane as eluent to obtain6-methyl-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-indene-4-carbaldehyde(Yield: 0.35 g, 79%) as white solid. LCMS (ES) m/z=357.19 [M+H]⁺; ¹H NMR(400 MHz, DMSO-d6) δ ppm: 2.07 (m, 2H), 2.24 (s, 6H), 2.99 (m, 2H), 3.19(m, 2H), 5.14 (s, 2H), 7.19 (d, J=7.2 Hz, 1H), 7.27-7.32 (m, 3H), 7.38(m, 1H), 7.44-7.49 (m, 3H), 7.56 (s, 1H), 10.01 (s, 1H).

Step-8: A solution of6-methyl-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-indene-4-carbaldehyde(100 mg, 0.28 mmol), (S)-piperidine-2-carboxylic acid (50 mg, 0.42 mmol)and acetic acid (1 drop) in DMF (2 mL) and MeOH (2 mL) was stirred atroom temperature for 2 h. Sodium cyanoborohydride (50 mg, 0.84 mmol) wasadded and the mixture was stirred for 16 h. After completion, thereaction mixture was concentrated and the residue was diluted with water(10 mL). The aqueous mixture was extracted with 10% MeOH in DCM (3×10mL). The combined organic layer was dried over sodium sulfate andconcentrated. The resulting crude was purified by flash chromatography(silica gel, 4 g) using 0-20% MeOH in DCM as eluent to obtain(S)-1-((6-methyl-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylicacid (Yield: 62 mg, 46%) as white solid. LCMS (ES) m/z=470.20 [M+H]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ ppm: 1.22-1.34 (m, 2H), 1.48 (m, 3H), 1.78 (m,2H), 1.99 (m, 2H), 2.19 (s, 3H), 2.23 (s, 3H), 2.83 (m, 1H), 2.88 (m,4H), 3.09 (m, 1H), 3.41 (d, J=12.8 Hz, 1H), 3.81 (d, J=12.8 Hz, 1H),4.94 (s, 2H), 6.97 (s, 1H), 7.19 (d, J=7.2 Hz, 1H), 7.27-7.32 (m, 3H),7.37 (m, 1H), 7.44-7.49 (m, 3H).

Example 5(S)-1-((6-chloro-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylicacid (5)

Step-1: To a solution of 4-hydroxy-2,3-dihydro-1H-inden-1-one (5.0 g,33.7 mmol) in 1,2-dichloroethane (500 mL) at room temperature undernitrogen atmosphere, sodium cyanoborohydride (8.48 g, 135 mmol) and ZnI₂(43 g, 135 mmol) were added slowly and the resulting mixture was heatedat 80° C. for 5 h. After completion of reaction, the reaction mixturewas filtered through silica gel bed in warm condition and washed withwarm DCM (500 mL). The filtrate was concentrated under vacuum to get2,3-dihydro-1H-inden-4-ol (Yield: 3.3 g, 75%) as brown viscous solidwhich was used in next step without further purification. ¹H NMR (400MHz, CDCl₃) δ ppm: 1.99 (m, 2H), 2.67 (m, 2H), 2.82 (m, 2H), 6.54 (d,J=7.6 Hz, 1H), 6.65 (d, J=7.6 Hz, 1H), 6.91 (t, J=7.6 Hz, 1H), 9.15 (s,1H).

Step-2: To a solution of 2,3-dihydro-1H-inden-4-ol (3.3 g, 24.6 mmol) inchloroform (150 mL) at 60° C., N-chlorosuccinimide (3.2 g, 24.6 mmol)was added. After stirring at room temperature for 1 h, conc.HCl (1 mL)was added and the mixture was refluxed for 10 h. After completion, thereaction mixture was cooled and diluted with water (100 mL). The aqueousmixture was extracted with DCM (2×100 mL) and the combined organic layerwas dried over sodium sulfate and concentrated. The crude was purifiedby flash chromatography (silica gel, 12 g) using 0 to 40% EtOAc inhexane as eluent to afford 5-chloro-2,3-dihydro-1H-inden-4-ol (Yield:1.3 g, 32%) as yellow liquid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 1.99 (m,2H), 2.82 (m, 4H), 6.69 (d, J=8.0 Hz, 1H), 7.07 (d, J=8.0 Hz, 1H), 9.24(s, 1H).

Step-3: To a solution of 5-chloro-2,3-dihydro-1H-inden-4-ol (1.3 g, 7.7mmol) in TFA (50 mL), hexamine (940 mg, 9.25 mmol) was added and themixture was heated at 120° C. for 2 h. After completion, the reactionmixture was quenched with solid sodium bicarbonate (5 g). After dilutingwith water (30 mL), the mixture was extracted with EtOAc (2×50 mL) andthe organic layer was dried over anhydrous sodium sulfate andconcentrated. The crude was purified by flash chromatography (silicagel) using 0 to 40% EtOAc in hexane as eluent to afford6-chloro-7-hydroxy-2,3-dihydro-1H-indene-4-carbaldehyde (Yield: 0.6 g,40%) as yellow liquid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 2.06 (m, 2H),2.83 (t, J=7.6 Hz, 2H), 3.16 (t, J=7.6 Hz, 2H), 7.69 (s, 1H), 9.87 (s,1H), 10.52 (bs, 1H).

Step-4: To a solution of6-chloro-7-hydroxy-2,3-dihydro-1H-indene-4-carbaldehyde (0.60 g, 3.06mmol) in acetonitrile (10 mL), potassium carbonate (0.63 g, 4.6 mmol)was added and the reaction mixture was stirred for 30 minutes. To thismixture, 3-(bromomethyl)-2-methyl-1,1′-biphenyl (0.79 g, 3.06 mmol) wasadded and was continued for 16 h. After completion of reaction, thereaction mixture was diluted with water (10 mL) and extracted with EtOAc(3×10 mL). The combined organic layer was dried over sodium sulfate andconcentrated. The resulting crude product was purified by flashchromatography (silica gel, 4 g) using 0-40% EtOAc in hexane as eluentto obtain6-chloro-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-indene-4-carbaldehyde(Yield: 0.70 g, 64%) as yellow solid. LCMS (ES) m/z=377.41 [M+H]⁺; H NMR(400 MHz, DMSO-d₆) δ ppm: 2.08 (m, 2H), 2.27 (s, 3H), 2.99 (t, J=7.6 Hz,2H), 3.19 (t, J=7.6 Hz, 2H), 5.14 (s, 2H), 7.21 (d, J=7.2 Hz, 1H),7.27-7.30 (m, 3H), 7.36 (m, 1H), 7.44-7.48 (m, 3H), 7.82 (s, 1H), 10.00(s, 1H).

Step-5: A solution of6-methyl-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-indene-4-carbaldehyde(120 mg, 0.30 mmol), (S)-piperidine-2-carboxylic acid (60 mg, 0.40 mmol)and acetic acid (1 drop) in DMF (2 mL) and MeOH (2 mL) was stirred atroom temperature for 2 h. Sodium cyanoborohydride (54 mg, 0.90 mmol) wasadded and the reaction mixture was stirred further for 16 h. Aftercompletion of the reaction, the reaction mixture was concentrated andthe residue was diluted with water (10 mL) and saturated sodiumbicarbonate solution (2 mL). The aqueous mixture was extracted withEtOAc (3×10 mL). The combined organic layer was dried over sodiumsulphate and concentrated. The resulting crude was purified by flashchromatography (silica gel, 4 g) using 0-20% MeOH in DCM as eluent toobtain(S)-1-((6-chloro-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylicacid (Yield: 80 mg, 57%) as white solid. LCMS (ES) m/z=490.14 [M+H]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ ppm: 1.22-1.34 (m, 2H), 1.48 (m, 3H), 1.75 (m,2H), 2.01 (m, 2H), 2.26 (s, 3H), 2.82-2.88 (m, 5H), 3.08 (m, 1H), 3.36(d, J=13.6 Hz, 1H), 3.74 (d, J=13.6 Hz, 1H), 5.04 (s, 2H), 7.20 (d,J=7.6 Hz, 1H), 7.25 (d, J=8.0 Hz, 1H), 7.27-7.32 (m, 3H), 7.37 (m, 1H),7.44-7.49 (m, 3H).

Example 6 Methyl7-(((2-acetamidoethyl)amino)methyl)-4-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-indene-5-carboxylate(6)

Step-1: To a solution of 4-hydroxy-2,3-dihydro-1H-indene-5-carbaldehyde(0.50 g, 3.08 mmol) in acetonitrile (20 mL), potassium carbonate (0.64g, 4.6 mmol) was added and the reaction mixture was stirred for 30minutes at room temperature. After stirring,3-(bromomethyl)-2-methyl-1,1′-biphenyl (0.79 g, 3.08 mmol) was added andthe reaction mixture was allowed to stir at room temperature for 6 h.After completion of reaction, the reaction mixture was diluted withwater (25 mL) and extracted with EtOAc (3×25 mL). The combined organiclayer was dried over sodium sulfate and concentrated. The resultingcrude was purified by flash chromatography (silica gel, 4 g) using 0-20%EtOAc in hexane as eluent to obtain4-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-indene-5-carbaldehyde(Yield: 1.05 g, 99.5%) as sticky solid. LCMS (ES) m/z=343.44 [M+H]⁺; ¹HNMR (400 MHz, CDCl₃) δ ppm: 2.13 (m, 2H), 2.28 (s, 3H), 2.98 (t, J=7.2Hz, 2H), 3.03 (t, J=7.2 Hz, 2H), 5.16 (s, 2H), 7.17 (d, J=7.2 Hz, 1H),7.31 (m, 2H), 7.35-7.38 (m, 2H), 7.38-7.44 (m, 4H), 7.70 (d, J=7.6 Hz,1H), 10.29 (s, 1H).

Step-2: To a solution of4-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-indene-5-carbaldehyde(0.80 g, 2.3 mmol) in acetonitrile (30 mL) and water (2 mL) at 0° C.,NaH₂PO₄ (112 mg, 0.9 mmol), 30% hydrogen peroxide solution (4 mL) andsodium chlorite (0.63 g, 7.0 mmol) were added successively. Afterstirring at 0° C. for 3 h, the reaction mixture was diluted with water(50 mL) and extracted with DCM (3×50 mL). The organic layer was washedwith brine (30 mL), dried over sodium sulfate and concentrated undervacuum to obtain4-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-indene-5-carboxylicacid (Yield: 0.80 g, 95%) as white solid. LCMS (ES) m/z=357.43 [M−H]⁻;¹H NMR (400 MHz, DMSO-d₆) δ ppm: 2.02 (m, 2H), 2.22 (s, 3H), 2.87 (m,4H), 5.06 (s, 2H), 7.04 (d, J=7.2 Hz, 1H), 7.17 (d, J=7.2 Hz, 1H),7.24-7.31 (m, 3H), 7.38 (m, 1H), 7.43-7.47 (m, 2H), 7.49-7.52 (m, 2H),12.77 (bs, 1H).

Step-3: To a solution of4-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-indene-5-carboxylicacid (0.30 g, 0.837 mmol) in acetone (10 mL), potassium carbonate (0.29g, 2.09 mmol) and methyl iodide (0.18 g, 1.26 mmol) were added. Thereaction mixture was heated to reflux for 4 h. After completion of thereaction, the reaction mixture was cooled and filtered. The filtrate wasconcentrated and the resulting crude was purified by flashchromatography (silica gel) using 5% EtOAc in hexane as eluent to obtainmethyl4-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-indene-5-carboxylate(Yield: 0.30 g, 96%) as white solid. LCMS (ES) m/z=373.18 [M+H]⁺; ¹H NMR(400 MHz, DMSO-d₆) δ ppm: 2.04 (m, 2H), 2.23 (s, 3H), 2.92 (m, 4H), 3.74(s, 3H), 5.03 (s, 2H), 7.10 (d, J=7.6 Hz, 1H) 7.18 (d, J=7.6 Hz, 1H),7.27 (m, 1H), 7.31 (d, J=7.6 Hz, 2H) 7.38 (m, 1H), 7.44-7.48 (m, 3H),7.54 (d, J=7.6 Hz, 1H).

Step-4: To a solution of methyl4-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-indene-5-carboxylate(0.20 g, 0.537 mmol) in TFA (5 mL), hexamine (0.112 g, 0.805 mmol) wasadded. The mixture was stirred at 120° C. for 3 h. After cooling themixture to 0° C., a 10% aqueous H₂SO₄ solution (5 mL) was added andheated at 100° C. for 2 h. The reaction mixture was cooled to roomtemperature and quenched with solid sodium bicarbonate until theeffervescence stopped. After diluting the mixture with water (25 mL), itwas extracted with DCM (3×50 mL) and the organic extract was dried oversodium sulfate and concentrated. The resulting crude was purified byflash chromatography (silica gel, 4 g) using 10% EtOAc in hexane toobtain methyl 7-formyl-4-hydroxy-2,3-dihydro-1H-indene-5-carboxylate(Yield: 80 mg, 67.6%) as white solid. LCMS (ES) m/z=221.32 [M+H]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ ppm: 2.10 (m, 2H), 2.83 (t, J=7.6 Hz, 2H), 3.25(t, J=7.6 Hz, 2H), 3.94 (s, 3H), 8.22 (s, 1H), 9.96 (s, 1H), 11.13 (bs,1H).

Step-5: To a solution of methyl7-formyl-4-hydroxy-2,3-dihydro-1H-indene-5-carboxylate (0.12 g, 0.54mmol) in acetonitrile (5 mL), potassium carbonate (0.11 g, 0.82 mmol)was added. The reaction mixture was stirred for 30 minutes. To thismixture, 3-(bromomethyl)-2-methyl-1,1′-biphenyl (0.14 g, 0.54 mmol) wasadded. The reaction mixture was stirred for 6 h. After completion ofreaction, the reaction mixture was diluted with water (10 mL) andextracted with EtOAc (3×25 mL). The combined organic layer was driedover sodium sulfate and concentrated. The resulting crude was purifiedby flash chromatography (silica gel, 4 g) using 0-10% EtOAc in hexane aseluent to obtain methyl7-formyl-4-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-indene-5-carboxylate(Yield: 70 mg, 58%) as off-white solid. LCMS (ES) m/z=401.14 [M+H]⁺.

Step-6: A solution of methyl7-formyl-4-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-indene-5-carboxylate(70 mg, 0.175 mmol), N-(2-aminoethyl)acetamide (30 mg, 0.26 mmol) andacetic acid (1 drop) in DMF (2.5 mL) and MeOH (2.5 mL) was stirred atroom temperature for 8 h. To this reaction mixture, sodiumcyanoborohydride (33 mg, 0.525 mmol) was added and the reaction mixturewas stirred further for 8 h. After completion of reaction, the reactionmixture was concentrated and the residue was diluted with water (10 mL)and extracted with DCM (3×10 mL). The combined organic layer was driedover sodium sulfate and concentrated. The resulting crude was purifiedby flash chromatography (silica gel, 4 g) using 0-20% MeOH in DCM aseluent to obtain methyl7-(((2-acetamidoethyl)amino)methyl)-4-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-indene-5-carboxylate(Yield: 33 mg, 41%) as sticky solid. LCMS (ES) m/z=487.21 [M+H]⁺; ¹H NMR(400 MHz, DMSO-d₆) δ ppm: 1.88 (s, 3H), 2.03 (m, 2H), 2.23 (s, 3H), 2.56(m, 2H), 2.91 (m, 4H), 3.14 (m, 2H), 3.64 (s, 2H), 3.76 (s, 3H), 5.01(s, 2H), 7.18 (d, J=7.2 Hz, 1H), 7.26-7.32 (m, 3H), 7.38 (m, 1H),7.44-7.48 (m, 3H), 7.55 (s, 1H), 7.77 (m, 1H).

Example 7(S)-1-((7-((3′-(3-(3,3-difluoropyrrolidin-1-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-methoxy-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylicacid (7)

Step-1: To a solution of 3-bromo-2-methylphenol (9.8 g, 52 mmol) in DMF(80 mL), 1,3-dichloropropane (11.73 g, 10 mmol) and potassium carbonate(21.5 g, 156 mmol) were added. The reaction mixture was stirred at 80°C. for 12 h under nitrogen atmosphere. After completion of the reaction,the mixture was cooled to room temperature and diluted with EtOAc (100mL), washed with ice cold water (50 mL) and brine (30 mL). The organicphase was dried over sodium sulphate and concentrated under vacuum togive a crude product. The resulting crude was purified by columnchromatography (silica gel, 100-200 mesh) using 10% EtOAc in hexanes toafford 1-(3-(3-bromo-2-methylphenoxy)propyl)-3,3-difluoropyrrolidine(Yield: 10.1 g, 73.7%) as yellow liquid. ¹H NMR (400 MHz, CDCl₃) δ ppm:2.25-2.31 (m, 5H), 3.77 (m, 2H), 4.12 (m, 2H), 6.80 (d, J=8.2 Hz, 1H),6.98-7.02 (m, 1H), 7.17 (d, J=8 Hz, 1H).

Step-2: To a stirred solution of1-bromo-3-(3-chloropropoxy)-2-methylbenzene (10.1 g, 38 mmol) in DMF (60mL), 3,3-difluoropyrrolidine (11 g, 76 mmol), potassium carbonate (22.5g, 163 mmol) and sodium iodide (8.5 g, 57 mmol) were added and thereaction mixture was heated at 80° C. for 12 h under nitrogenatmosphere. After completion of the reaction, the reaction mixture wascooled to room temperature and diluted with EtOAc (100 mL), washed withice cold water (50 mL), brine (50 mL) and the organic phase was driedover sodium sulphate and concentrated under vacuum to give a crudeproduct. The resulting crude was purified by column chromatography(silica gel, 100-200 mesh) using 15% EtOAc in hexane to afford1-(3-(3-bromo-2-methylphenoxy)propyl)-3,3-difluoropyrrolidine (7.1 g,56.3%) as yellow liquid. ¹H NMR (400 MHz, CDCl₃) δ ppm: 1.96 (m, 2H),2.22-2.33 (m, 5H), 2.66 (m, 2H), 2.75 (m, 2H), 2.94 (m, 2H), 4.01 (m,2H), 6.78 (d, J=8.0 Hz, 1H), 6.96-7.00 (m, 1H), 7.15 (d, J=8.0 Hz, 1H).

Step-3: To a solution of1-(3-(3-bromo-2-methylphenoxy)propyl)-3,3-difluoropyrrolidine (2 g,0.059 mol) and(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol(1.78 g, 71 mmol) in toluene:ethanol:water (1:1:1) (30 mL) at roomtemperature, potassium carbonate (2.47 g, 17 mmol) was added and thereaction mixture was purged with nitrogen for 15 minutes. To thismixture, Pd(dppf)Cl₂-DCM (0.24 g, 0.29 mmol) was added and reactionmixture was again purged with nitrogen for 10 min and heated at 95° C.for 12 h. After completion of the reaction, the reaction mixture wascooled to room temperature and filtered through celite pad. The filtratewas diluted with water (100 mL) and the mixture was extracted with EtOAc(2×500 mL). The organic layer was washed with brine (500 mL), dried oversodium sulfate and concentrated to get crude compound. The resultingcrude was purified by column chromatography (silica gel, 100-200 mesh)using 10% EtOAc in hexane as eluent to afford(3′-(3-(3,3-difluoropyrrolidin-1-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methanol(Yield: 2 g, 90%) as off white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm:1.77 (s, 3H), 1.94 (s, 3H), 2.20-2.32 (m, 4H), 2.62-2.68 (m, 4H), 2.92(m, 2H), 4.06 (m, 2H), 4.54 (m, 2H), 5.09 (m, 1H), 6.64 (d, J=7.44 Hz,1H), 6.94 (d, J=7.84 Hz, 2H), 7.15-7.22 (m, 2H), 7.39 (d, J=7.44 Hz,1H).

Step-4: To a stirred solution of(3′-(3-(3,3-difluoropyrrolidin-1-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methanol(0.55 g, 14 mmol) and7-hydroxy-5-methoxy-2,3-dihydro-1H-indene-4-carbaldehyde (0.28 g, 14mmol) in dry THF (20 mL) under nitrogen atmosphere at 0° C.,triphenylphosphine (0.96 g, 35 mmol), and DEAD (1.15 g, 66 mmol) wereadded and the reaction mixture was stirred at room temperature for 24 h.After completion of the reaction, the mixture was diluted with EtOAc (50mL) and washed with ice cold water (20 mL) and brine (20 mL). Theorganic phase was dried over sodium sulphate, concentrated under vacuumto give crude product which was purified by column chromatography(silica gel, 100-200 mesh) using 30% EtOAc in hexane to afford7-((3′-(3-(3,3-difluoropyrrolidin-1-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-methoxy-2,3-dihydro-1H-indene-4-carbaldehyde(Yield: 0.110 g, 13%) as white solid. LCMS (ES) m/z=550.25 [M+H]⁺.

Step-5: A solution of7-((3′-(3-(3,3-difluoropyrrolidin-1-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-methoxy-2,3-dihydro-1H-indene-4-carbaldehyde(100 mg, 0.185 mmol), (S)-piperidine-2-carboxylic acid (36 mg, 0.27mmol) and acetic acid (1 drop) in DMF (2 mL) and MeOH (2 mL) was stirredat room temperature for 2 h. To this mixture, sodium cyanoborohydride(34 mg, 0.55 mmol) was added and the reaction mixture was stirred for 16h. After completion of the reaction, the reaction mixture was dilutedwith ice cold water (10 mL) and the aqueous mixture was extracted with10% MeOH in DCM (3×100 mL). The combined organic layer was dried oversodium sulfate and concentrated. The resulting crude was purified byPrep-TLC using 10% MeOH in DCM as solvent system toobtain(S)-1-((7-((3′-(3-(3,3-difluoropyrrolidin-1-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-methoxy-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylicacid (36, Yield: 50 mg, 44%) as white solid. LCMS: (ES) m/z=663.31[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 1.76 (m, 2H), 1.82 (s, 3H),1.90-2.00 (m, 9H), 2.19 (m, 4H), 2.50-2.72 (m, 7H), 2.75-2.89 (m, 5H),2.98-3.11 (m, 2H), 3.73 (m, 1H), 3.80 (s, 3H), 3.89 (m, 1H), 4.05 (m,2H), 5.18 (s, 2H), 6.63 (s, 1H), 6.86 (d, J=7.48 Hz, 1H), 6.96 (d,J=8.16 Hz, 1H), 7.06 (d, J=7.36 Hz, 1H), 7.17-7.28 (m, 2H), 7.47 (d,J=7.52 Hz, 1H).

Example 8(S)-1-((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylicacid(8)

Step-1: A mixture of 7-hydroxy-5-methoxy-2,3-dihydro-1H-inden-1-one (20g, 0.1122 mol) in DCE (200 mL), zinc iodide (107.48 g, 0.337 mol) andsodium cyanoborohydride (28.21 g, 0.448 mol) were heated at 75° C. for 8h. The reaction mixture was filtered and the residue was washed with DCM(200 mL). The filtrate was washed with water (100 mL), brine (100 mL)and dried over anhydrous sodium sulfate and concentrated under vacuum.The resulting crude was purified by column chromatography (silica gel,100-200 mesh) using 30% EtOAc in hexane as eluent to obtain6-methoxy-2,3-dihydro-1H-inden-4-ol (Yield: 17 g, 92%) as white solid.LCMS (ES) m/z=165.04 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 1.95 (m,2H), 2.65 (t, J=7.2 Hz, 2H), 2.76 (t, J=7.6 Hz, 2H), 3.64 (s, 3H), 6.14(s, 1H), 6.27 (s, 1H), 9.11 (s, 1H).

Step-2: To a solution of 6-methoxy-2,3-dihydro-1H-inden-4-ol (1 g, 0.006mol) in 10% aqueous NaOH solution (45 mL), O-cyclodextrin (8 g, 0.007mol) was added and the mixture was heated to 60° C. To this mixture,chloroform (6 mL, 0.125 mol) was added slowly for 3 h. After consumptionof starting material, reaction mixture was cooled to room temperatureand acidified with 1N HCl solution to pH=2. The aqueous layer wasextracted with EtOAc (3×200 mL) and the combined organic layer was driedover sodium sulfate and concentrated. The crude was purified by flashchromatography (silica gel) using 30% EtOAc in hexane as eluent toobtain 7-hydroxy-5-methoxy-2,3-dihydro-1H-indene-4-carbaldehyde (Yield:200 mg, 17%) as off-white solid. LCMS (ES) m/z=193.03 [M+H]⁺; ¹H NMR(400 MHz, DMSO-d₆) δ ppm: 1.99 (m, 2H), 2.64 (t, J=7.2 Hz, 2H), 3.08 (t,J=7.6 Hz, 2H), 3.80 (s, 3H), 6.36 (s, 1H), 10.24 (s, 1H), 10.45 (s, 1H).

Step-3: To a solution of7-hydroxy-5-methoxy-2,3-dihydro-1H-indene-4-carbaldehyde (600 mg, 3.12mmol) in DCM (100 mL) at 0° C., 1M BBr₃ solution in DCM (4.7 mL, 4.68mmol) was added slowly and the solution was allowed to stir at roomtemperature for 6 h. After completion, the reaction mixture was quenchedwith water (100 mL) and extracted with DCM (2×100 mL). The organic layerwas dried over anhydrous sodium sulfate and concentrated. The resultingcrude product was purified by flash chromatography using 30% EtOAc inhexane as eluent to obtain5,7-dihydroxy-2,3-dihydro-1H-indene-4-carbaldehyde (Yield: 405 mg, 71%)as white solid. LCMS (ES) m/z=177.28 [M−H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δppm: 2.00 (m, 2H), 2.63 (t, J=7.2 Hz, 2H), 3.08 (t, J=7.6 Hz, 2H), 6.177(s, 1H), 9.97 (s, 1H), 10.59 (s, 1H), 11.10 (s, 1H).

Step-4: To a solution of5,7-dihydroxy-2,3-dihydro-1H-indene-4-carbaldehyde (0.40 g, 2.247 mmol)in acetonitrile (20 mL), potassium carbonate (0.37 g, 2.69 mmol) and3-(bromomethyl)-2-methyl-1,1′-biphenyl (0.59 g, 2.25 mmol) were added.The reaction mixture was stirred at room temperature for 16 h. Aftercompletion, the reaction mixture was diluted with water (20 mL) andextracted with EtOAc (3×20 mL). The combined organic layer was driedover sodium sulfate and concentrated. The resulting crude was purifiedby flash chromatography (silica gel, 4 g) using 0-20% EtOAc in hexane aseluent to obtain5-hydroxy-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-indene-4-carbaldehyde(Yield: 0.70 g, 87%) as white solid. LCMS (ES) m/z=359.35 [M+H]⁺; ¹H NMR(400 MHz, DMSO-d₆) δ ppm: 2.05 (m, 2H), 2.19 (s, 3H), 2.71 (t, J=7.2 Hz,2H), 3.14 (t, J=7.2 Hz, 2H), 5.24 (s, 2H), 6.55 (s, 1H), 7.21 (d, J=7.6Hz, 1H), 7.28-7.33 (m, 3H), 7.38 (m, 1H), 7.44-7.48 (m, 3H), 10.05 (s,1H), 11.31 (s, 1H).

Step-5: To a solution of5-hydroxy-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-indene-4-carbaldehyde(0.50 g, 1.39 mmol) in acetonitrile (20 mL), potassium carbonate (0.35g, 2.5 mmol) and 3-(chloromethyl)benzonitrile (0.41 g, 2.0 mmol) wereadded. The reaction mixture was stirred at room temperature for 16 h.After completion, the reaction mixture was diluted with water (20 mL)and extracted with EtOAc (3×30 mL). The combined organic layer was driedover sodium sulfate and concentrated. The resulting crude was purifiedby flash chromatography (silica gel, 4 g cartridge) using 0-30% EtOAc inhexane as eluent to obtain3-(((4-formyl-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)benzonitrile(Yield: 0.505 g, 75%) as white solid. LCMS (ES) m/z=474.41 [M+H]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ ppm: 2.00 (m, 2H), 2.21 (s, 3H), 2.70 (t, J=7.2Hz, 2H), 3.13 (t, J=7.2 Hz, 2H), 5.30 (s, 2H), 5.38 (s, 2H), 6.92 (s,1H), 7.22 (d, J=7.6 Hz, 1H), 7.27-7.33 (m, 3H), 7.38 (m, 1H), 7.44-7.48(m, 3H), 7.63 (t, J=7.6 Hz, 1H), 7.85 (m, 2H), 8.01 (s, 1H), 10.39 (s,1H).

Step-6: A solution of3-(((4-formyl-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)benzonitrile(100 mg, 0.21 mmol), (S)-piperidine-2-carboxylic acid (40.8 mg, 0.32mmol), sodium cyanoborohydride (66.4 mg, 1.06 mmol) and acetic acid (2drops) in DMF (5 mL) was stirred at 70° C. for 4 h. After completion,the reaction mixture was poured on to ice-cold water (10 mL). The solidwas filtered and dissolved in DCM. The organic solvent was dried oversodium sulfate and concentrated. The resulting crude was purified byflash chromatography (silica gel, 4 g cartridge) using 0-10% MeOH in DCMas eluent to obtain(S)-1-((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylicacid (Yield: 26 mg, 46%) as white solid. LCMS (ES) m/z=587.15 [M+H]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ ppm: 1.32-1.45 (m, 4H), 1.78 (m, 2H), 1.97 (m,2H), 2.20 (s, 3H), 2.32 (m, 1H), 2.73 (m, 2H), 2.81 (m, 1H), 2.94-3.03(m, 2H), 3.14 (m, 1H), 3.71 (d, J=12.4 Hz, 1H), 3.88 (d, J=12.4 Hz, 1H),5.14 (s, 2H), 5.23 (s, 2H), 6.73 (s, 1H), 7.19 (d, J=7.6 Hz, 1H),7.25-7.33 (m, 3H), 7.37 (m, 1H), 7.44-7.49 (m, 3H), 7.61 (t, J=7.6 Hz,1H), 7.80 (d, J=7.2 Hz, 1H), 7.86 (d, J=7.2 Hz, 1H), 7.98 (s, 1H).

Example 9 Synthesisof(S)-1-((5-((5-fluoropyridin-3-yl)methoxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylicacid

Step-1: To a solution of5-hydroxy-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-indene-4-carbaldehyde(0.40 g, 1.117 mmol) in DMF (20 mL), potassium carbonate (0.46 g, 3.38mmol) and 3-(chloromethyl)-5-fluoropyridine (0.325 g, 2.25 mmol) wasadded and stirred at room temperature for 16 h. After completion, thereaction mixture was diluted with water (20 mL) and extracted with EtOAc(3×30 mL). The combined organic layer was dried over sodium sulfate andconcentrated. The resulting crude was purified by flash chromatography(silica gel, 4 g cartridge) using DCM as eluent to obtain5-((5-fluoropyridin-3-yl)methoxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-indene-4-carbaldehyde(Yield: 0.201 g, 38%) as white solid. LCMS (ES) m/z=468.16 [M+H]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ ppm: 1.99-2.00 (m, 2H), 2.22 (s, 3H), 2.71 (m,2H), 3.13 (m, 2H), 5.32 (s, 2H), 5.40 (s, 2H), 6.95 (s, 1H), 7.22 (d,J=7.6 Hz, 1H), 7.27-7.40 (m, 4H), 7.44-7.48 (m, 3H), 7.92 (d, J=9.2 Hz,1H), 8.58 (s, 1H), 8.62 (s, 1H), 10.35 (s, 1H).

Step-2: To a solution of5-((5-fluoropyridin-3-yl)methoxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-indene-4-carbaldehyde(50 mg, 0.11 mmol), (S)-piperidine-2-carboxylic acid (52 mg, 0.32 mmol)in MeOH (3 mL) and DMF (3 mL), sodium cyanoborohydride (19 mg, 0.32mmol) and acetic acid (2 drops) were added and the mixture was stirredat room temperature for 8 h. After completion, the reaction mixture wasdiluted with water (10 mL) and extracted with DCM (3×30 mL). The organiclayer was dried over anhydrous sodium sulphate and concentrated. Theresulting crude was purified by flash chromatography (silica gel, 4 gcartridge) using 0-10% MeOH in DCM as eluent to obtain(S)-1-((5-((5-fluoropyridin-3-yl)methoxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylicacid (Yield: 30 mg, 48%) as white solid. LCMS (ES) m/z=581.47 [M+H]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ ppm: 1.32-1.45 (m, 4H), 1.75 (m, 2H), 1.97 (m,2H), 2.32 (m, 3H), 2.49 (m, 1H), 2.74 (m, 2H), 2.81-3.05 (m, 3H), 3.14(m, 1H), 3.68 (d, J=12.8 Hz, 1H), 3.88 (d, J=12.4 Hz, 1H), 5.16 (s, 2H),5.26 (m, 2H), 6.78 (s, 1H), 7.19 (d, J=7.6 Hz, 1H), 7.25-7.33 (m, 3H),7.39 (m, 1H), 7.44-7.47 (m, 3H), 7.92 (d, J=9.6 Hz, 1H), 8.54 (s, 1H),8.61 (s, 1H).

Example 10N-(2-(((5-((5-fluoropyridin-3-yl)methoxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)amino)ethyl)acetamidewas prepared by following procedure similar to Example 9

LCMS (ES) m/z=554.44 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 1.75 (s,3H), 1.97-2.01 (m, 2H), 2.20 (m, 3H), 2.61 (m, 2H), 2.76 (m, 2H), 2.89(m, 2H), 3.13 (m, 2H), 3.71 (s, 2H), 5.16 (s, 2H), 5.26 (m, 2H), 6.77(s, 1H), 7.19 (d, J=7.6 Hz, 1H), 7.25-7.33 (m, 3H), 7.39 (m, 1H),7.44-7.47 (m, 3H), 7.80 (bs, 1H), 7.86 (d, J=9.2 Hz, 1H), 8.55 (s, 1H),8.59 (s, 1H).

Example 11 Synthesis of(S)-5-((5-methoxy-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)-5-azaspiro[2.4]heptane-6-carboxylicacid

Step-1: To a solution of(S)-5-(tert-butoxycarbonyl)-5-azaspiro[2.4]heptane-6-carboxylic acid(1.0 g, 3.6 mmol) in 1,4-dioxane (10 mL) at 0° C., 4M HCl in 1,4-dioxane(15 mL) was added drop wise and allowed the mixture to stir at roomtemperature for 3 h. After completion, the reaction mixture wasconcentrated under vacuum to obtain(S)-5-azaspiro[2.4]heptane-6-carboxylic acid hydrochloride (700 mg,crude) as off-white solid. LCMS (ES) m/z=142.28 [M+H]⁺; ¹H NMR (400 MHz,DMSO-d₆) δ ppm: 0.64 (m, 4H), 1.97-2.02 (m, 1H), 2.22 (m, 1H), 3.12 (m,2H), 4.44 (m, 1H), 8.91 (bs, 1H), 10.24 (bs, 1H).

Step-2: A solution of5-methoxy-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-indene-4-carbaldehyde(200 mg, 0.42 mmol), (S)-5-azaspiro[2.4]heptane-6-carboxylic acidhydrochloride (89 mg, 0.50 mmol) and acetic acid (2 drops) in MeOH (2.5mL) and DMF (2.5 mL) was stirred at room temperature for 30 minutes. Tothis mixture, sodium cyanoborohydride (39 mg, 0.63 mmol) was added andcontinued stirring at room temperature for 16 h. After completion, thereaction mixture was diluted with water (10 mL) and extracted with 10%MeOH in DCM (3×15 mL). The organic layer was dried over anhydrous sodiumsulfate and concentrated. The resulting crude was purified by flashchromatography (silica gel, 4 g cartridge) using 0-10% MeOH in DCM aseluent, to obtain(S)-5-((5-methoxy-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)-5-azaspiro[2.4]heptane-6-carboxylicacid (Yield: 90 mg, 45%) as white solid. LCMS (ES) m/z=498.43 [M+H]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ ppm: 0.46 (m, 1H), 0.58-0.64 (m 3H), 1.81-1.99(m, 1H), 1.99-2.04 (m, 2H), 2.22 (s, 3H), 2.36 (m, 1H), 2.75 (m, 2H),2.86-3.06 (m, 4H), 3.85 (m, 1H), 3.86 (s, 3H), 4.15 (m, 2H), 5.21 (s,2H), 6.72 (s, 1H), 7.20 (d, J=7.6 Hz, 1H), 7.28-7.33 (m, 3H), 7.39 (m,1H), 7.44-7.50 (m, 3H).

Example 12 Synthesis of(S)-1-((7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-5-(2,2,2-trifluoroethoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylicacid

Step-1: To a solution of trifluoroethanol (500 mg, 5.0 mmol) in DCM (10mL), triethylamine (1.5 g, 15 mmol) was added and cooled to 0° C. Tothis mixture, p-toluene sulfonyl chloride (1.2 g, 6.0 mmol) was addedand allowed the reaction mixture to stir at room temperature for 6 h.After completion, the reaction mixture was diluted with water (10 mL)and separated the layers. The aqueous layer was further extracted withEtOAc (2×10 mL) and the combined organic layer was dried over anhydroussodium sulfate and concentrated. The crude was purified by flashchromatography (silica gel, 12 g cartridge) using 20% EtOAc in hexanesas eluent to obtain 2,2,2-trifluoroethyl 4-methylbenzenesulfonate(Yield: 405 mg, 31%) as oil. ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 2.44 (s,3H), 4.86 (m, 2H), 7.52 (d, J=8.0 Hz, 2H), 7.86 (d, J=8.0 Hz, 2H).

Step-2: To a solution of5-hydroxy-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-indene-4-carbaldehyde(0.40 g, 1.12 mmol) and 2,2,2-trifluoroethyl 4-methylbenzenesulfonate(0.34 g, 1.34 mmol) in DMF (8 mL), potassium carbonate (0.28 g, 2.0mmol) was added and stirred the mixture at room temperature for 16 h.After completion, the mixture was diluted with water (20 mL) andextracted with EtOAc (3×25 mL). The organic layer was dried over sodiumsulfate and concentrated. The crude was purified by flash chromatography(silica gel, 12 g cartridge) using 20% EtOAc in hexanes as eluent toobtain7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-5-(2,2,2-trifluoroethoxy)-2,3-dihydro-1H-indene-4-carbaldehyde(Yield: 102 mg, 21%) as white solid. LCMS (ES) m/z=441.57 [M+H]⁺.

Step-3: A solution of7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-5-(2,2,2-trifluoroethoxy)-2,3-dihydro-1H-indene-4-carbaldehyde(100 mg, 0.23 mmol), (S)-piperidine-2-carboxylic acid (87 mg, 0.68mmol), sodium cyanoborohydride (42.2 mg, 0.68 mmol) and acetic acid (2drops) in MeOH (2 mL) and DMF (3 mL) was stirred at room temperature for16 h. After completion, the reaction mixture was diluted with water (10mL) and extracted with 10% MeOH in DCM (3×25 mL). The organic layer wasdried over anhydrous sodium sulfate and concentrated. The residue wasdiluted with DCM (10 mL) and washed with DM water (4 mL). The organiclayer was concentrated and purified by reverse phase HPLC using method-Ato obtain(S)-1-((7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-5-(2,2,2-trifluoroethoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylicacid (Yield: 20 mg, 16%) as white solid. LCMS (ES) m/z=554.47 [M+H]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ ppm: 1.47 (m, 1H), 1.60 (m, 3H), 1.73 (m, 1H),2.03 (m, 3H), 2.21 (s, 3H), 2.79 (m, 2H), 2.83 (bs, 1H), 3.11 (m, 3H),3.85 (bs, 1H), 3.95-4.02 (m, 2H), 4.84 (m, 2H), 5.20 (s, 2H), 6.86 (s,1H), 7.21 (d, J=7.6 Hz, 1H), 7.28-7.33 (m, 3H), 7.39 (m, 1H), 7.44-7.47(m, 3H).

Example 13 Synthesis ofN-(2-(((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)amino)ethyl)-N-methylacetamide

Step-5: To a solution of3-(((4-formyl-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)benzonitrile(135 mg, 0.29 mmol), N-(2-aminoethyl)-N-methylacetamide (100 mg, 0.86mmol) in 1:1 mixture of MeOH and DMF (5 mL), acetic acid (2 drops) wasadded and stirred for 15 minutes. To this mixture, sodiumcyanoborohydride (53 mg, 0.86 mmol) was added and continued stirring thereaction mixture at room temperature for 16 h. After completion, thereaction mixture was diluted with water (10 mL) and extracted with 10%MeOH in DCM (3×25 mL). The organic layer was dried over sodium sulfateand concentrated. The resulting crude was purified by flashchromatography (silica gel, 4 g cartridge) using 0-10% MeOH in DCM aseluent to obtainN-(2-(((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)amino)ethyl)-N-methylacetamide(Yield: 46 mg, 28%) as white solid. LCMS (ES) m/z=574.54 [M+H]⁺; ¹H NMR(400 MHz, DMSO-d₆) δ ppm: 1.72 (s, 3H), 1.97 (m, 2H), 2.09 (s, 3H), 2.20(s, 3H), 2.36 (m, 2H), 2.74 (m, 2H), 2.88 (m, 2H), 3.13 (m, 2H), 3.40(s, 2H), 5.13 (s, 2H), 5.20 (s, 2H), 6.72 (s, 1H), 7.19 (d, J=7.6 Hz,1H), 7.25 (m, 1H), 7.33 (m, 2H), 7.37 (m, 1H), 7.44-7.49 (m, 3H),7.59-7.61 (m, 2H), 7.81 (t, J=8.8 Hz, 2H), 7.95 (s, 1H).

Example 14 Synthesis ofN-(2-(((5-(1-(3-cyanophenyl)ethoxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)amino)ethyl)acetamide

Step-1: To a solution of5-hydroxy-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-indene-4-carbaldehyde(0.250 g, 0.68 mmol) in DMF (10 mL), potassium carbonate (0.192 g, 1.39mmol) and 3-(1-bromoethyl)benzonitrile (0.22 g, 1.04 mmol) were addedand stirred the reaction mixture at room temperature for 10 minutes.After completion, the reaction mixture was diluted with water (20 mL)and extracted with EtOAc (3×30 mL). The combined organic layer was driedover sodium sulfate and concentrated. The resulting crude was purifiedby flash chromatography (silica gel, 4 g cartridge) using 0-20% EtOAc inhexane as eluent to obtain3-(1-((4-formyl-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)benzonitrile(Yield: 0.275 g, 80%) as white solid. LCMS (ES) m/z=488.34 [M+H]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ ppm: 1.63 (d, J=6.4 Hz, 3H), 1.97 (m, 2H), 2.18(s, 3H), 2.65 (m, 2H), 3.08 (m, 2H), 5.10 (d, J=12.4 Hz, 1H), 5.26 (d,J=12.4 Hz, 1H), 5.86 (m, 1H), 6.73 (s, 1H), 7.27 (m, 2H), 7.30-7.40 (m,4H), 7.44-7.48 (m, 2H), 7.55 (t, J=7.6 Hz, 1H), 7.74 (d, J=7.6 Hz, 1H),7.83 (d, J=7.6 Hz, 1H), 8.01 (s, 1H), 10.45 (s, 1H).

Step-2: A solution of3-(1-((4-formyl-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)benzonitrile(150 mg, 0.31 mmol), N N-(2-aminoethyl)acetamide (47 mg, 0.46 mmol) in1:1 mixture of MeOH and DMF (5 mL), acetic acid (5 drops) was added andstirred for 15 minutes. To this mixture, sodium cyanoborohydride (38 mg,0.62 mmol) was added and continued stirring the reaction mixture at roomtemperature for 16 h. After completion, the reaction mixture was dilutedwith water (10 mL) and extracted with 10% MeOH in DCM (3×25 mL). Theorganic layer was dried over sodium sulfate and concentrated. Theresulting crude was purified by flash chromatography (silica gel, 4 gcartridge) using 0-10% MeOH in DCM as eluent to obtainN-(2-(((5-(1-(3-cyanophenyl)ethoxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)amino)ethyl)acetamide(Yield: 55 mg, 31%) as white solid. LCMS (ES) m/z=574.51 [M+H]⁺; ¹H NMR(400 MHz, DMSO-d₆) δ ppm: 1.57 (d, J=6.4 Hz, 3H), 1.78 (s, 3H),1.94-1.97 (m, 2H), 2.15 (s, 3H), 2.61 (m, 2H), 2.67-2.75 (m, 2H), 2.86(m, 2H), 3.16 (m, 2H), 3.69 (bs, 2H), 4.89 (d, J=12.0 Hz, 1H), 5.07 (d,J=12.4 Hz, 1H), 5.60 (m, 1H), 6.46 (s, 1H), 7.15-7.22 (m, 2H), 7.25-7.31(m, 3H), 7.37 (m, 1H), 7.44-7.48 (m, 2H), 7.54 (t, J=7.6 Hz, 1H), 7.73(d, J=7.6 Hz, 1H), 7.78 (d, J=7.6 Hz, 1H), 7.82 (bs, 1H), 7.94 (s, 1H).

Example 15 Synthesis ofN-(1-((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidin-3-yl)acetamide

Step-1: A solution of3-(((4-formyl-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)benzonitrile(150 mg, 0.40 mmol), N-(piperidin-3-yl)acetamide (170 mg, 1.20 mmol) intriethylamine (82 mg) and acetic acid (5 drops) was stirred for 1 h. Tothis mixture, sodium cyanoborohydride (74.6 mg, 1.20 mmol) was added andcontinued stirring the reaction mixture at room temperature for 16 h.After completion, the reaction mixture was diluted with water (10 mL)and extracted with EtOAc (3×25 mL). The organic layer was dried oversodium sulfate and concentrated. The resulting crude was purified byflash chromatography (silica gel, 4 g cartridge) using 0-10% MeOH in DCMas eluent to obtainN-(1-((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidin-3-yl)acetamide(Yield: 23 mg, 9.5%) as white solid. LCMS (ES) m/z=600.55 [M+H]⁺; ¹H NMR(400 MHz, DMSO-d₆) δ ppm: 1.10 (m, 1H), 1.39 (m, 1H), 1.58-1.74 (m, 6H),1.83-1.99 (m, 3H), 2.21 (s, 3H), 2.61.2.76 (m, 4H), 2.88 (m, 2H), 3.39(m, 2H), 3.60 (m, 1H), 5.13 (s, 2H), 5.20 (s, 2H), 6.72 (s, 1H), 7.20(d, J=7.52 Hz, 1H), 7.25-7.33 (m, 3H), 7.37 (m, 1H), 7.43-7.47 (m, 3H),7.63 (m, 2H), 7.80 (d, J=7.36 Hz, 1H), 7.86 (d, J=7.52 Hz, 1H), 7.97 (s,1H).

The following compounds were prepared following procedures describedabove

TABLE 2 LCMS m/z ¹H NMR (400 MHz, S. No. Structure [M + H]⁺ DMSO-d₆) δppm 16

  429.3 1.78 (s, 3H), 1.98-2.02 (m, 2H), 2.18 (s, 3H), 2.64-2.66 (m,2H), 2.81 (t, J = 7.2 Hz, 2H), 2.88 (t, J = 7.4 Hz, 2H), 3.16-3.18 (m,2H), 3.70 (s, 2H), 5.13 (s, 2H), 6.89 (d, J = 8.4 Hz, 1H), 7.11 (d, J =8.4 Hz, 1H), 7.17 (d, J = 7.6 Hz, 1H), 7.23-7.31 (m, 3H), 7.34-N-(2-(((7-((2-methyl- 7.46 (m, 4H), 7.81 (s, 1H) [1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro- 1H-inden-4- yl)methyl)amino)ethyl) acetamide 17

  426.3 1.96-1.99 (m, 2H), 2.18 (s, 3H), 2.79-2.81 (m, 4H), 3.26- 3.31(m, 6H), 4.58 (s, 4H), 5.11 (s, 2H), 6.85 (bs, 1H), 6.99 (bs, 1H),7.16-7.18 (m, 1H), 7.24-7.38 (m, 4H), 7.42- 7.44 (m, 3H)6-((7-((2-methyl-[1,1′- biphenyl]-3-yl)methoxy)- 2,3-dihydro-1H-inden-4-yl)methyl)-2-oxa-6- azaspiro[3.3]heptane 18

  448.0 1.99-2.01 (m, 2H), 2.18 (s, 3H), 2.81-2.89 (m, 4H), 3.30 (s,6H), 3.65 (bs, 2H), 4.32 (bs, 3H), 5.12 (s, 2H), 6.81- 6.89 (m, 1H),7.04-7.20 (m, 2H), 7.22-7.39 (m, 4H), 7.42- 7.44 (m, 3H)2-(hydroxymethyl)-2-(((7- ((2-methyl-[1,1′- biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4- yl)methyl)amino)propane- 1,3-diol 19

  428.2 0.86-0.87 (m, 2H), 1.08-1.09 (m, 2H), 1.94-2.02 (m, 2H), 2.17(s, 3H), 2.77-2.88 (m, 4H), 3.73 (s, 2H), 5.11 (s, 2H), 6.83 (d, J = 7.6Hz, 1H), 7.03 (d, J = 8.4 Hz, 1H), 7.16 (d, J = 7.6 Hz, 1H), 7.23-7.37(m, 4H), 7.42-7.45 (m, 3H) (((7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)- 2,3-dihydro-1H-inden-4- yl)methyl)amino)cyclo-propane-1-carboxylic acid 20

  402.1 1.98-2.02 (m, 2H), 2.18 (s, 3H), 2.80-2.94 (m, 4H), 3.08 (s,2H), 3.86 (s, 2H), 5.15 (s, 2H), 6.94 (d, J = 8.0 Hz, 1H), 7.16-7.21(m,2H), 7.23-7.31 (m, 3H), 7.36-7.37 (m, 1H), 7.42-7.44 (m, 3H)((7-((2-methyl-[1,1′- biphenyl]-3-yl)methoxy)- 2,3-dihydro-1H-inden-4-yl)methyl)glycine 21

  417.2 1.98-2.02 (m, 2H), 2.18 (s, 3H), 2.25-2.28 (m, 2H), 2.80- 2.91(m, 6H), 3.74 (s, 2H), 5.13 (s, 2H), 6.90 (d, J = 8.0 Hz, 1H), 7.09-7.17(m, 2H), 7.23-7.37 (m, 4H), 7.42-7.44 (m, 3H), 8.01-9.91 (bs, 2H)3-(((7-((2-methyl-[1,1′- biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4- yl)methyl)amino)propanoic acid 22

  417.2 1.94-1.99 (m, 2H), 2.17 (s, 3H), 2.22 (s, 3H), 2.79 (t, J = 7.6Hz, 2H), 2.84-2.91 (m, 4H), 3.53 (s, 2H), 5.10 (s, 2H), 6.84 (d, J = 8.4Hz, 1H), 7.04 (d, J = 8.4 Hz, 1H), 7.45 (d, J = 7.6 Hz, 1H), 7.22-7.30(m, 3H), 7.33-7.44 (m, 4H) N-methyl-N-((7-((2- methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro- 1H-inden-4- yl)methyl)glycine 23

  430.2 1.15-1.16 (m, 3H), 2.00-2.05 (m, 2H), 2.10-2.25 (m, 5H),2.81-2.95 (m, 4H), 3.09-3.11 (m, 1H), 3.73 (d, J = 12.8 Hz, 1H), 3.87(d, J = 12.8 Hz, 1H), 5.15 (s, 2H), 6.93 (d, J = 8.0 Hz, 1H), 7.12-7.18(m, 2H), 7.24-7.37 (m, 4H), 7.42-7.44 (m, 2H), 9.98 (bs, 1H)3-(((7-((2-methyl-[1,1′- biphenyl]-3-yl)methoxy)- 2,3-dihydro-1H-inden-4- yl)methyl)amino)butanoic acid 24

  415.2 1.25-1.26 (m, 3H), 1.98-2.02 (m, 2H), 2.18 (s, 3H), 2.80- 2.97(m, 4H), 3.16-3.18 (m, 1H), 3.78-3.90 (m, 2H), 5.15 (s, 2H), 6.94 (d, J= 8.0 Hz, 1H), 7.16-7.37 (m, 6H), 7.42- 7.44 (m, 2H), 7.56-8.34 (bs, 1H)((7-((2-methyl-[1,1′- biphenyl]-3-yl)methoxy)- 2,3 -dihydro-1H-inden-4-yl)methyl)alanine 25

  488.5 1.13-1.19 (m, 1H), 1-98-2.0 (m, 3H), 2.15-2.23 (m, 1H), 2.21 (s,3H), 2.74 (t, J = 7.6 Hz, 3H), 2.89-2.97 (m, 2H), 3.19 (bs, 1H), 3.74(bs, 1H), 3.83 (s, 3H), 4.07-4.08 (m, 2H), 4.23 (bs, 1H), 4.19 (s, 2H),4.21 (bs, 1H), 6.69 (s, 1H), 7.19-7.21 (m, 1H), 7.26- 7.31 (m, 3H),7.34-7.38 (m, 1H), 7.42-7.49 (m, 3H) (2S,4R)-4-hydroxy-1-((5-methoxy-7-((2-methyl- [1,1′-biphenyl]-3- yl)methoxy)-2,3-dihydro-1H-inden-4- yl)methyl)pyrrolidine-2- carboxylic acid 26

  486.5 1.35-1.51 (m, 4H), 1.75 (bs, 2H), 1.96 (t, J = 7.2 Hz, 3H), 2.20(s, 3H), 2.52 (s, 2H), 2.73 (t, J = 7.6 Hz, 2H), 2.68- 2.78 (m, 1H),2.79-2.93 (m, 1H), 3.10-3.11 (m, 1H), 3.71- 3.74 (m, 1H), 3.78 (s, 3H),3.82-3.84 (m, 1H), 5.17 (s, 2H), 6.64 (s, 1H), 7.18 (d, J = 7.6 Hz, 1H),7.25-7.31 (m, 3H), 7.34-7.38 (m, 1H), 7.42- 7.48 (m, 3H)(S)-1-((5-methoxy-7-((2- methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro- 1H-inden-4- yl)methyl)piperidine-2- carboxylicacid 27

  468.2 1.47(bs, 2H), 1.63-1.70 (m, 8H), 2.03 (bs, 2H), 2.18 (s, 3H),2.65 (bs, 2H), 2.80-2.89 (m, 1H), 3.07 (bs, 1H), 3.86 (bs, 2H), 4.21(bs, 1H), 5.13 (s, 2H), 6.86-7.14 (m, 1H), 7.19-7.26 (m, 2H), 7.27-7.38(m, 4H), 7.42-.47 (m, 3H)1.47(bs, 2H), 1.63-1.70 (m, 8H), 2.03 (bs, 2H),2.18 (s, 3H), 2.65 (bs, 3H), 2.80- 1-((4-((2-methyl-[1,1′- 2.89 (m, 2H),3.07 (bs, 1H), biphenyl]-3-yl)methoxy)- 3.86 (bs, 2H), 4.21 (bs, 1H),5,6,7,8- 5.13 (s, 1H), 6.86-7.14 (m, tetrahydronaphthalen-1- 1H),7.19-7.26 (m, 2H), 7.27- yl)methyl)piperidine-2- 7.38 (m, 4H), 7.42-.47(m, carboxylic acid 3H) 28

  443.20 1.96-1.99 (m, 2H), 2.18 (s, 3H), 2.79-2.81 (m, 4H), 3.26- 3.31(m, 6H), 4.58 (s, 4H), 5.11 (s, 2H), 6.85 (bs, 1H), 6.99 (bs, 1H),7.16-7.18 (m, 1H), 7.24-7.38 (m, 4H), 7.42- 7.44 (m, 3H)N-(2-(((6-methy1-7-((2- methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro- 1H-inden-4- yl)methyl)amino)ethyl) acetamide 29

  472.18 1.99 (m, 4H), 2.19 (s, 3H), 2.23 (s, 3H), 2.43 (m, 1H),2.83-2.93 (m, 5H), 3.16 (m, 1H), 3.50 (m, 1H), 3.60 (d, J = 12.8 Hz,1H), 3.99 (d, J = 12.8 Hz, 1H), 4.21 (bs, 1H), 4.95 (s, 2H), 5.01 (bs,1H), 6.99 (s, 1H), 7.19 (d, J = 7.2 Hz, 1H), 7.27-7.32 (m, 3H), 7.37 (m,1H), 7.44-7.49 (2S,4R)-4-hydroxy-1-((6- (m, 3H).methyl-7-((2-methyl-[1,1′- bipheny1]-3-yl)methoxy)-2,3-dihydro-1H-inden-4- yl)methyl)pyrrolidine-2- carboxylic acid 30

  463.17 1.79 (s, 3H), 2.01 (m, 2H), 2.27 (s, 3H), 2.54 (m, 2H), 2.83(m, 2H), 2.89 (m, 2H), 3.14 (m, 2H), 3.60 (s, 2H), 5.03 (s, 2H), 7.19(d, J = 7.2 Hz, 1H), 7.26-7.32 (m, 4H), 7.38 (m, 1H), 7.44-7.48 (m, 3H),7.80 (bs, 1H). N-(2-(((6-chloro-7-((2- methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro- 1H-inden-4- yl)methyl)amino)ethyl) acetamide 31

  492.09 1.99 (m, 4H), 2.27 (s, 3H), 2.23 (m, 1H), 2.83-2.93 (m, 4H),3.16 (m, 1H), 3.50 (m, 1H), 3.60 (d, J = 12.8 Hz, 1H), 3.99 (d, J = 12.8Hz, 1H), 4.21 (bs, 1H), 4.9 (bs, 1H), 5.05 (s, 2H), 7.21 (d, J = 7.2 Hz,1H), 7.28 (s, 2H), 7.29-7.32 (m, 2H), 7.37 (m, 1H), 7.44-7.49 (m, 3H),11.0- (2S,4R)-1-((6-chloro-7- 13.0 (bs, 1H). ((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)- 2,3-dihydro-1H-inden-4- yl)methyl)-4-hydroxypyrrolidine-2- carboxylic acid 32

  636.92 1.76 (s, 3H), 1.82 (s,3H) 1.87-2.00 (m, 5H), 2.01 (s 3H),2.20-2.28 (m, 4H), 2.75- 2.59 (m, 6H), 2.83-2.92 (m, 4H), 3.06 (m, 2H),3.55 (s, 2H), 3.76 (s, 3H), 4.05 (m, 2H), 5.16 (s, 2H), 6.59 (s, 1H),6.68 (d, J = 7.48 Hz, 1H), 6.96 (d, J = 8.16 Hz, 1H), 7.06 (d, J = 7.36Hz, 1H), 7.17-7.28 (m, 2H), 7.47 (bs, 1H). N-(2-(((7-((3′-(3-(3,3-difluoropyrrolidin-1- yl)propoxy)-2,2′- dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5- methoxy-2,3-dihydro-1H- inden-4- yl)methyl)amino)ethyl)acetamide 33

  665.241 1.82(s, 2H), 1.90-2.09 (m, 8H), 2.10-2.30 (m, 4H), 2.55- 3.00(m, 11H), 3.10-3.49 (bs, 2H), 3.60 (m, 1H), 3.83 (s, 3H), 4.00-4.09 (m,4H), 4.11 (m, 1H), 5.20 (m, 3H), 6.86 (m, 2H), 6.96 (d, J = 8.16 Hz,1H), 7.06 (d, J = 7.36 Hz, 1H), 7.17-7.28 (m, 2H), 7.47 (d, J = 7.52 Hz,1H). (2S,4R)-1-((7-((3′-(3-(3,3- difluoropyrrolidin-1- yl)propoxy)-2,2'-dimethyl-[1,1′-biphenyl]- 3-yl)methoxy)-5- methoxy-2,3-dihydro-1H-inden-4-yl)methyl)-4- hydroxypyrrolidine-2- carboxylic acid 34

  560.30 1.76 (s, 3H), 1.99 (m, 2H), 2.20 (s, 3H), 2.66 (m, 2H), 2.76(m, 2H), 2.90 (m, 2H), 3.16 (m, 2H), 3.77 (s, 2H), 5.14 (s, 2H), 5.24(s, 2H), 6.74 (s, 1H), 7.18 (d, J = 7.6 Hz, 1H), 7.26 (t, J = 7.6 Hz,1H), 7.31 (d, J = 7.2 Hz, 2H), 7.36-7.48 (m, 4H), 7.61 (t, J = 7.2 Hz,1H), 7.82 (d, J = 7.2 Hz, 2H), 7.84 (bs, 1H) 7.97 (s, 1H) N-(2-(((5-((3-cyanobenzyl)oxy)-7-((2- methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro- 1H-inden-4- yl)methyl)amino)ethyl) acetamide 35

  589.28 1.99-2.10 (m, 4H), 2.20 (s, 3H), 2.73 (m, 2H), 2.83-3.02 (m,3H), 3.30 (m, 2H), 3.73 (m, 1H), 4.12-4.20 (m, 2H), 4.26 (bs, 1H), 5.16(s, 2H), 5.31 (s, 2H), 6.78 (s, 1H), 7.19 (d, J = 7.2 Hz, 1H), 7.26 (d,J = 7.6 Hz, 1H), 7.32 (d, J = 7.2 Hz, 2H), 7.36-7.49 (m, 4H), 7.61 (t, J= 7.6 Hz, 1H), 7.80 (d, J = 7.6 Hz, 1H), 7.90 (d, J = 7.6 Hz, 1H), 8.03(s, 1H). (2S,4R)-1-((5-((3- cyanobenzyl)oxy)-7-((2-methyl-[1,1′-biphenyl]-3- yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)-4- hydroxypyrrolidine-2- carboxylic acid 36

  587.15 1.45 (m, 4H), 1.76 (m, 2H), 1.97 (m, 2H), 2.20 (s, 3H), 2.32(m, 2H), 2.66-3.14 (m, 4H), 3.32 (m, 1H), 3.73 (m, 1H), 3.90 (m, 1H),5.13 (s, 2H), 5.23 (s, 2H), 6.73 (s, 1H), 7.20 (d, J = 7.44 Hz, 1H),7.24-7.32 (m, 3H), 7.37- 7.45 (m, 4H), 7.60 (m, 1H), 7.80 (d, J = 7.26Hz, 1H), 7.87 (d, J = 7.32 Hz, 1H), 7.98 (s, 1H). (S)-1-((5-((3-cyanobenzyl)oxy)-7-((2- methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro- 1H-inden-4- yl)methyl)piperidine-2- carboxylicacid 37

  586.55 1.49-1.58 (m, 4H), 1.73 (m, 1H), 1.91-1.97 (m, 4H), 2.19 (s,3H), 2.59-2.74 (m, 4H), 2.82 (m, 1H), 2.98 (m, 1H), 3.19 (d, J = 12.5Hz, 1H), 3.69 (d, J = 12 Hz, 1H), 5.10 (s, 2H), 5.24 (s, 2H), 6.69 (s,1H), 6.95 (bs, 1H), 7.06 (bs, 1H), 7.19 (m, 1H), 7.25 (m, 1H), 7.32 (m,2H), 7.36-7.47 (m, 4H), 7.59 (m, 1H), 7.78- 7.82 (m, 2H), 7.93 (s, 1H).(S)-1-((5-((3- cyanobenzyl)oxy)-7-((2- methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro- 1H-inden-4- yl)methyl)piperidine-2- carboxamide38

  579.39 1.97 (m, 2H), 2.19 (s, 3H), 2.74 (m, 2H), 2.90 (m, 2H), 3.41(s, 6H), 3.69 (bs, 2H), 4.22 (bs, 3H), 5.13 (s, 2H), 5.21 (s, 2H), 6.72(s, 1H), 7.19 (m, 1H), 7.25 (m, 1H), 7.32 (m, 2H), 7.36-7.47 (m, 4H),7.59 (m, 1H), 7.78 (d, J = 7.96 Hz, 1H), 7.90 (d, J = 7.88 Hz, 1H), 7.97(s, 1H). (((4-(((1,3-dihydroxy-2- (hydroxymethyl)propan-2-yl)amino)methyl)-7-((2- methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro- 1H-inden-5- yl)oxy)methyl) benzonitrile 39

  557.41 1.97 (m, 2H), 2.19 (s, 3H), 2.74 (m, 2H), 2.86 (m, 2H), 3.23(m, 2H), 3.31 (m, 2H), 3.45 (m, 2H), 4.55 (s, 4H), 5.13 (s, 2H), 5.22(s, 2H), 6.72 (s, 1H), 7.19 (m, 1H), 7.25 (m, 1H), 7.32 (m, 2H),7.39-7.47 (m, 4H), 7.62 (m, 1H), 7.84 (m, 2H), 7.98 (s, 1H).3-(((4-((2-oxa-6- azaspiro[3.3]heptan-6- yl)methyl)-7-((2-methyl-[1,1′-biphenyl]-3- yl)methoxy)-2,3-dihydro- 1H-inden-5- yl)oxy)methyl)benzonitrile 40

  559.41 1.23-1.33 (m, 4H), 1.35 (m, 1H), 1.56 (m, 1H), 1.69-1.84 (m,3H), 1.98 (m, 2H), 2.21 (s, 3H), 2.74-2.76 (m, 3H), 2.87 (m, 2H), 3.45(m, 1H), 4.49 (bs, 1H), 5.13 (s, 2H), 5.21 (s, 2H), 6.72 (s, 1H), 7.20(d, J = 7.32 Hz, 1H), 7.25-7.32 (m, 3H), 7.39 (m, 1H), 7.44-7.47 (m,3H), 7.63 (m, 1H), 7.80 (d, J = 7.68 Hz, 1H), 7.85 (d, J = 7.85 Hz, 1H),7.94 (s, 1H). (((4-((3-hydroxypiperidin- 1-yl)methyl)-7-((2-methyl-[1,1′-biphenyl]-3- yl)methoxy)-2,3-dihydro- 1H-inden-5-yl)oxy)methyl) benzonitrile 41

  533.49 2.00 (m, 2H), 2.19 (s, 3H), 2.76 (m, 2H), 2.92 (m, 2H), 3.07(s, 2H), 3.99 (s, 2H), 5.16 (s, 2H), 5.27 (s, 2H), 6.76 (s, 1H), 7.19(d, J = 7.44 Hz, 1H), 7.27 (m, 1H), 7.32 (d, J = 7.24 Hz, 1H), 7.36-7.47 (m, 4H), 7.60 (m, 1H), 7.81 (d, J = 7.52 Hz, 1H), 7.91 (d, J = 7.76Hz, 1H), 8.02 (s, 1H). ((5-((3-cyanobenzyl)oxy)- 7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)- 2,3-dihydro-1H-inden-4- yl)methyl)glycine 42

599.49 0.43-0.54 (m, 4H), 1.77 (m, 1H), 2.00 (m, 2H), 2.20 (s, 3H), 2.31(m, 1H), 2.75 (m, 2H), 2.88-2.92 (m, 4H), 3.60 (m, 1H), 4.12 (m, 2H),5.16(m, 2H), 5.31 (m, 2H), 6.79 (s, 1H), 7.20 (d, J = 7.32 Hz, 1H), 7.27(m, 1H), 7.32 (d, J = 7.12 Hz, 2H), 7.39 (m, 1H), 7.44-7.47 (m, 3H),7.67 (m, 1H), 7.83 (d, J = 7.62 Hz, 1H), 7.91 (d, J =7.8 Hz, 1H), 8.02(s, 1H). (S)-5-((5-((3- cyanobenzyl)oxy)-7-((2-methyl-[1,1′-biphenyl]-3- yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)-5- azaspiro[2.4]heptane-6- carboxylic acid 43

  599.55 1.20-1.40 (m, 4H), 1.58 (m, 1H), 1.71-1.79 (m, 2H), 1.95 (m,2H), 2.19 (s, 3H), 2.32 (m, 2H), 2.72-2.79 (m, 3H), 3.00(m, 1H), 3.60(d, J = 12.48 Hz, 1H), 3.67 (d, J = 12.52 Hz, 1H), 5.11(m, 2H), 5.31 (m,2H), 6.72 (s, 1H), 7.19 (d, J = 7.12 Hz, 1H), 7.27 (m, 1H), 7.32 (d, J =7 Hz, 2H), 7.39 (m, 2H), 7.44- 7.47 (m, 2H), 7.61 (m, 1H), 7.80 (m, 2H),7.92 (s, 1H), 11.90 (bs, 1H). rac-(1R,6S)-2-((5-((3-cyanobenzyl)oxy)-7-((2- methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H- nden-4-yl)methyl)-2-azabicyclo[4.1.0]heptane-1- carboxylic acid (cis, racemic) 44

  561.46 1.66 (m, 2H), 2.00 (m, 2H), 2.23 (m, 6H), 2.76 (m, 4H), 2.93(m, 2H), 3.81 (s, 2H), 5.16 (s, 2H), 5.24 (s, 2H), 6.76 (s, 1H),7.26-7.45 (m, 9H), 7.61 (m, 1H), 7.80-7.85 (m, 2H), 7.99 (s, 1H).(((5-((3- cyanobenzyl)oxy)-7-((2- methyl-[1,1′-biphenyl]-3- yl)methoxy)-2,3-dihydro- 1H-inden-4- yl)methyl)amino)butanoic acid 45

  498.49 1.15-1.33 (m, 2H), 1.37 (m, 2H), 1.62 (m, 1H), 1.78 (m, 1H),2.01 (m, 2H), 2.18 (m, 3H), 2.32 (m, 1H), 2.76 (m, 2H), 2.95 (m, 1H),3.09 (s, 1H), 3.49 (m, 2H), 3.59 (m, 2H), 3.84 (s, 3H), 5.20 (s, 2H),6.71 (s, 1H), 7.21 (d, J = 7.44 Hz, 1H), 7.27-7.31 (m, 3H), 7.37 (m,1H), 7.44-7.50 (m, 3H) (1R,6S)-2-((5-methoxy-7- ((2-methyl-[1,1′-biphenyl]-3-yl) methoxy)- 2,3-dihydro-1H-inden-4- yl)methyl)-2-azabicyclo [4.1.0]heptane-1- carboxylic acid (cis, racemic)

Example 46 Synthesis of(S)-1-((5-((5-cyanopyridin-3-yl)methoxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylic acid

Step-1: To a solution of5-hydroxy-7((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-indene-4-carbaldehyde(0.20 g, 0.55 mmol) in acetonitrile (20 mL), potassium carbonate (0.30g, 2.23 mmol) and 5-(chloromethyl)nicotinonitrile (5, 0.25 g, 1.67 mmol)was added and stirred the reaction mixture at RT for 16 h. Aftercompletion, the reaction mixture was diluted with water (20 mL) andextracted with EtOAc (3×30 mL). The combined organic layer was driedover sodium sulfate and concentrated. The resulting crude was purifiedby flash chromatography (silica gel, 4 g cartridge) using 0-30% EtOAc inhexane as eluent to obtain5-(((4-formyl-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)nicotinonitrile(Yield: 0.07 g, 26%) as white solid. LCMS (ES) m/z=475.47 [M+H]⁺; ¹H NMR(400 MHz, DMSO-d₆) δ ppm: 1.97-2.00 (m, 2H), 2.21 (s, 3H), 2.71 (m, 2H),3.13 (m, 2H), 5.32 (s, 2H), 5.42 (s, 2H), 6.92 (s, 1H), 7.22 (d, J=7.6Hz, 1H), 7.29-7.40 (m, 3H), 7.44-7.48 (m, 3H), 8.52 (s, 1H), 9.01 (s,2H), 10.37 (s, 1H).

Step-6: A solution of5-(((4-formyl-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)nicotinonitrile(100 mg, 0.21 mmol), (S)-piperidine-2-carboxylic acid (40.8 mg, 0.32mmol), sodium cyanoborohydride (66.4 mg, 1.06 mmol) and acetic acid (2drops) in DMF (5 mL), the reaction mixture was stirred at 70° C. for 4h. After completion, the reaction mixture was poured on ice cold water(10 mL) and collected the white solid by filtration. A solution of whitesolid in DCM (20 mL) was dried over sodium sulfate and concentrated. Theresulting crude was purified by flash chromatography (silica gel, 4 gcartridge) using 0-10% MeOH in DCM as eluent. The product was furtherpurified by reverse phase HPLC using method-B to obtain(S)-1-((5-((5-cyanopyridin-3-yl)methoxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylicacid (Yield: 26 mg, 46%) as white solid. LCMS (ES) m/z=588.38 [M+H]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ ppm: 1.32-1.45 (m, 4H), 1.75 (m, 2H), 1.97 (m,2H), 2.21 (s, 3H), 2.32 (m, 1H), 2.76 (m, 2H), 2.81-3.03 (m, 3H), 3.11(m, 1H), 3.68 (d, J=12.28 Hz, 1H), 3.88 (d, J=12.4 Hz, 1H), 5.14 (s,2H), 5.28 (m, 2H), 6.77 (s, 1H), 7.19 (d, J=7.6 Hz, 1H), 7.25-7.33 (m,3H), 7.39 (m, 1H), 7.44-7.47 (m, 3H), 8.48 (s, 1H), 9.01 (m, 1H).

Following compounds were prepared by following similar to aboveprocedures

TABLE 3 LCMS m/z ¹H NMR (400 MHz, S. No. Structure [M + H]⁺ DMSO-d₆) δppm 47

  590.35 1.96-2.10 (m, 5H), 2.20 (s, 3H), 2.73 (m, 2H), 2.83-3.02 (m,2H), 3.27 (bs, 1H), 3.66 (m, 1H), 4.16 (m, 2H), 4.23 (m, 1H), 5.18 (m,3H), 5.36 (m, 2H), 6.81 (s, 1H), 7.20 (m, 1H), 7.29 (m, 1H), 7.33 (m,2H), 7.36- 7.47 (m, 4H), 8.53 (s, 1H), 9.03 (m, 2H) (2S,4R)-1-((5-((5-cyanopyridin-3-yl)methoxy)- 7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro- 1H-inden-4-yl)methyl)-4-hydroxypyrrolidine-2- carboxylic acid 48

  561.39 1.76 (s, 3H), 1.99 (m, 2H), 2.20 (s, 3H), 2.62 (m, 2H), 2.78(m, 2H), 2.90 (m, 2H), 3.11-3.16 (m, 2H), 3.73 (s, 2H), 5.15 (s, 2H),5.28 (s, 2H), 6.76 (s, 1H), 7.18 (d, J = 7.6 Hz, 1H), 7.24 (t, J = 7.6Hz, 1H), 7.31 (d, J = 7.2 Hz, 2H), 7.36-7.48 (m, 4H), 7.80 (bs, 1H),8.43(s, 1H), 8.99 (s, 2H). N-(2-(((5-((5-cyanopyridin-3-yl)methoxy)-7-((2-methyl- [1,1′-biphenyl]-3- yl)methoxy)-2,3-dihydro-1H-inden-4- yl)methyl)amino)ethyl) acetamide 49

  579.39 1.97 (m, 2H), 2.20 (s, 3H), 2.77 (m, 2H), 2.91 (m, 2H), 3.39(s, 6H), 3.66 (bs, 2H), 4.00-4.50 (bs, 3H), 5.14 (s, 2H), 5.26 (s, 2H),6.75 (s, 1H), 7.17 (m, 1H), 7.28 (m, 1H), 7.36 (m, 2H), 7.39 (m, 1H),7.43-7.47 (m, 3H), 8.45 (s, 1H), 9.00 (s, 2H). (((4-(((1,3-dihydroxy-2-(hydroxymethyl)propan-2- yl)amino)methyl)-7-((2-methyl-[1,1′-biphenyl]-3- yl)methoxy)-2,3-dihydro- 1H-inden-5-yl)oxy)methyl)nicotinonitrile 50

  588.42 1.98 (m, 2H), 2.21 (s, 3H), 2.87 (m, 2H), 2.92- 2.94 (m, 1H),2.96-3.00 (m, 2H), 3.09 (bs, 1H), 3.43 (m, 1H), 3.50-3.64 (m, 4H), 3.80(m, 2H), 5.14 (s, 2H), 5.26 (m, 2H), 6.75 (s, 1H), 7.20 (d, J = 7.28 Hz,1H), 7.28 (m, 1H), 7.33 (d, J = 7.04 Hz, 2H), 7.37 (m 1H), 7.39-7.47 (m,3H), 8.44 (s, 1H), 9.01 (d, J = 10.5 Hz, 2H), 12.32 (bs, 1H).(S)-4-((5-((5-cyanopyridin-3- yl)methoxy)-7-((2-methyl-[1,1′-biphenyl]-3- yl)methoxy)-2,3-dihydro- 1H-inden-4-yl)methyl)morpholine-3- carboxylic acid 51

  600.57 1.09-1.40 (m, 4H), 1.56 (m, 1H), 1.70 (m, 1H), 1.78 (m, 1H),1.96-1.99 (m, 2H), 2.20 (s, 3H), 2.32-2.40 (m, 2H), 2.73-2.82 (m, 3H),2.99-3.05 (m, 1H), 3.63 (m, 2H), 5.15 (s, 2H), 5.32 (s, 2H), 6.78 (s,1H), 7.19 (d, J = 7.28 Hz, 1H), 7.27 (m, 1H), 7.33 (d, J = 7.04 Hz, 2H),7.37-7.47 (m, 4H), 8.41 (s, 1H), 8.96 (m, 1H), 8.99 (m, 2H), 11.73 (bs,1H). rac-(1R,6S)-2-((5-((5- cyanopyridin-3-yl)methoxy)-7-((2-methyl-[1,1′-biphenyl]-3- yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)-2- azabicyclo[4.1.0]heptane-1- carboxylic acid (cis,racemic) 52

  600.52 0.41 (m, 1H), 0.53 (m, 3H), 1.75-1.79 (m, 1H), 1.99-2.01 (m,2H), 2.21 (s, 3H), 2.31 (m, 1H), 2.76 (m, 2H), 2.89-3.31 (m, 4H), 3.60(m, 1H), 4.13 (m, 2H), 5.18 (m, 2H), 5.33 (m, 2H), 6.83 (s, 1H), 7.19(m, 1H), 7.29 (m, 1H), 7.33 (m, 2H), 7.38 (m, 1H), 7.40- 7.48 (m, 3H),8.55 (s, 1H), 9.02 (m, 1H), 9.05 (m, 1H) (S)-5-((5-((5-cyanopyridin-3-yl)methoxy)-7-((2-methyl- [1,1′-biphenyl]-3- yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)-5- azaspiro[2.4]heptane-6- carboxylic acid

Synthesis ofN-(2-(((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)(methyl)amino)ethyl)acetamide

Step-1: To a stirred solution ofN-(2-(((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)amino)ethyl)acetamide(1, 0.3 g, 0.523 mmol) in DMF (8 mL), formaldehyde (64.4 mg, 2.14 mmol)and formic acid (98 mg, 2.14 mmol) were added and stirred for 15minutes. To this mixture, sodium cyanoborohydride (133 mg, 2.14 mmol)was added and stirred the reaction mixture for 4 h at room temperature.After completion, the reaction mixture was diluted with water (10 mL)and extracted with 10% DCM in MeOH (3×25 mL). The combined organic layerwas dried over anhydrous sodium sulfate and concentrated. The cruderesidue was purified by flash chromatography (silica gel, 4 g cartridge)using 0-10% MeOH in DCM as eluent followed by recrystallized from THFand pentane to obtainN-(2-(((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)(methyl)amino)ethyl)acetamide(Yield: 68 mg, 21%) as white solid. LCMS (ES) m/z=574.60 [M+H]⁺; ¹H NMR(400 MHz, DMSO-d₆) δ ppm: 1.72 (s, 3H), 1.95-1.99 (m, 2H), 2.09 (s, 3H),2.21 (s, 3H), 2.36 (m, 2H), 2.74 (t, J=7.2 Hz, 2H), 2.88 (t, J=7.4 Hz,2H), 3.12 (m, 2H), 3.40 (s, 2H), 5.13 (s, 2H), 5.21 (s, 2H), 6.73 (s,1H), 7.19 (d, J=7.6 Hz, 1H), 7.23-7.31 (m, 3H), 7.37 (m, 1H), 7.44-7.48(m, 3H), 7.59-7.63 (m, 2H), 7.81 (t, J=8.4 Hz, 2H), 7.95 (s, 1H).

Example 54 Synthesis ofN-(2-(((5-((4-cyanobenzyl)oxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)amino)ethyl)acetamide

Step-1: Preparation of4-(((4-formyl-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)benzonitrile

To a solution of5-hydroxy-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-indene-4-carbaldehyde(1, 0.30 g, 0.83 mmol) in DMF (10 mL), potassium carbonate (0.34 g, 2.4mmol) and 4-(chloromethyl)benzonitrile (0.16 g, 0.83 mmol) was added andstirred the reaction mixture at RT for 16 h. After completion, thereaction mixture was diluted with water (20 mL) and extracted with EtOAc(3×30 mL). The combined organic layer was dried over sodium sulfate andconcentrated. The resulting crude was purified by flash chromatography(silica gel, 4 g cartridge) using 0-30% EtOAc in hexane as eluent toobtain3-(((4-formyl-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)benzonitrile(Yield: 0.35 g, 89.27%) as white solid.

LCMS (ES) m/z=474.41 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 2.00 (m,2H), 2.21 (s, 3H), 2.70 (t, J=7.2 Hz, 2H), 3.13 (t, J=7.2 Hz, 2H), 5.30(s, 2H), 5.38 (s, 2H), 6.92 (s, 1H), 7.22 (d, J=7.6 Hz, 1H), 7.27-7.33(m, 3H), 7.38 (m, 1H), 7.44-7.48 (m, 3H), 7.63 (t, J=7.6 Hz, 1H), 7.85(m, 2H), 8.01 (s, 1H), 10.39 (s, 1H).

Step-2:N-(2-(((5-((4-cyanobenzyl)oxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)amino)ethyl)acetamide

A solution of4-(((4-formyl-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)benzonitrile (150 mg, 0.31 mmol), N-(2-aminoethyl)acetamide(32 mg, 0.31 mmol), and acetic acid (2 drops) in DMF (3 mL) and MeOH (3mL) was stirred at RT for 2 h. To this mixture, sodium cyanoborohydride(60 mg, 0.93 mmol) was added and stirred the reaction mixture for 16 h.After completion, the reaction mixture was poured on ice cold water (10mL) and collected the white solid by filtration. A solution of whitesolid in DCM (20 mL) was dried over sodium sulfate and concentrated. Theresulting crude was purified by flash chromatography (silica gel, 4 gcartridge) using 0-10% MeOH in DCM as eluent to obtainN-(2-(((5-((4-cyanobenzyl)oxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)amino)ethyl)acetamide(Yield: 90 mg, 52%) as white solid. LCMS (ES) m/z=560.49 [M+H]⁺; ¹H NMR(400 MHz, DMSO-d₆) δ ppm: 1.77 (s, 3H), 1.99 (m, 2H), 2.20 (s, 3H),2.74-2.78 (m, 4H), 2.90 (m, 2H), 3.21 (m, 2H), 3.85 (bs, 2H), 5.14 (m,2H), 5.29 (s, 2H), 6.74 (s, 1H), 7.20 (d, J=7.48 Hz, 1H), 7.25 (t, J=7.6Hz, 1H), 7.31 (d, J=7.08 Hz, 2H), 7.36-7.48 (m, 4H), 7.70 (d, J=5.92 Hz,2H), 7.87 (d, J=8.16 Hz, 2H), 7.92 (bs, 1H).

Example 55 Synthesis of(S)-1-((7-((2-cyano-[1,1′-biphenyl]-3-yl)methoxy)-5-methoxy-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylicacid

Step-1: To a solution of7-hydroxy-5-methoxy-2,3-dihydro-1H-indene-4-carbaldehyde (918 mg, 4.7mmol) and 3-(hydroxymethyl)-[1,1′-biphenyl]-2-carbonitrile (1.0 g, 4.7mmol) in dry THF (30 mL), triphenyl phosphine (3 g, 0.035 mol) was addedand cooled the mixture to 0° C. To this mixture, DEAD (266 mg, 0.014mol) and stirred the mixture for 2 h. After completion, the reactionmixture was diluted with water (50 mL) and extracted with EtOAc (3×100mL). The organic layer was dried over sodium sulphate and concentrated.The resulting crude was purified by flash chromatography (silica gel, 12g cartridge) using 0-20% EtOAc in hexanes as eluent to obtain3-(((7-formyl-6-methoxy-2,3-dihydro-1H-inden-4-yl)oxy)methyl)-[1,1′-biphenyl]-2-carbonitrile(Yield: 450 mg, 24.5%) as white solid. LCMS (ES) m/z=384.44 [M+H]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ ppm: 1.95-2.01 (m, 2H), 2.71 (m, 2H), 3.11 (m,2H), 4.04 (s, 3H), 5.50 (s, 2H), 6.79 (s, 1H), 7.48-7.65 (m, 6H),7.78-7.84 (m, 2H), 10.30 (s, 1H).

Step-2: To a solution of3-(((7-formyl-6-methoxy-2,3-dihydro-1H-inden-4-yl)oxy)methyl)-[1,1′-biphenyl]-2-carbonitrile(60 mg, 0.156 mmol) and (S)-piperidine-2-carboxylic acid (26 mg, 0.20mmol) in DMF (3 mL), acetic acid (3 drops) was added and stirred thereaction mixture for 10 minutes. To this mixture, sodiumcyanoborohydride (29 mg, 0.47 mmol) was added and stirred at 70° C. for3 h. After completion, the reaction mixture was diluted with ice coldwater (10 mL) and collected the resulting solid by filtration. The solidwas further dissolved in DCM (30 mL) and dried over sodium sulphate andconcentrated. The residue was purified by flash chromatography (silicagel, 4 g cartridge) using 0-10% MeOH in DCM as eluent to obtain(S)-1-((7-((2-cyano-[1,1′-biphenyl]-3-yl)methoxy)-5-methoxy-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylicacid (Yield: 15 mg, 19%) as white solid. LCMS (ES) m/z=497.25 [M+H]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ ppm: 1.48 (m, 4H), 1.77 (m, 2H), 1.95-2.01 (m,2H), 2.73 (m, 2H), 2.83 (m, 1H), 2.92 (m, 1H), 3.07 (m, 2H), 3.14 (m,1H), 3.74 (m, 1H), 3.79 (s, 3H), 3.88 (m 1H), 5.36 (s, 2H), 6.65 (s,1H), 7.48-7.62 (m, 6H), 7.77 (t, J=7.2 Hz, 1H), 7.82 (t, J=7.6 Hz, 1H).

Following compounds were prepared by following similar to aboveprocedures

LCMS m/z ¹H NMR (400 MHz, S. No. Structure [M + H]⁺ DMSO-d₆) δ ppm 56

  470.32 1.78 (s, 3H), 1.95-1.99 (m, 2H), 2.57 (m, 2H), 2.77 (m, 2H),2.87 (m, 2H), 3.14 (m, 2H), 3.64 (bs, 2H), 3.79 (s, 3H), 5.35 (s, 2H),6.63 (s, 1H), 7.50-7.61 (m, 6H), 7.75-7.84 (m, 3H).N-(2-(((7-((2-cyano-[1,1′- biphenyl]-3-yl)methoxy)-5-methoxy-2,3-dihydro- 1H-inden-4- yl)methyl)amino)ethyl) acetamide 57

  499.31 1.95-1.99 (m, 3H), 2.09 (m, 1H), 2.77 (m, 3H), 2.87-2.99 (m,2H), 3.26 (m, 1H), 3.65 (m, 1H), 3.84 (s, 3H), 4.08 (m, 2H), 4.23 (bs,1H), 5.26 (bs, 1H), 5.38 (s, 2H), 6.69 (s, 1H), 7.50-7.61 (m, 6H),7.75-7.84 (m, 2H). (2S,4R)-1-((7-((2-cyano- [1,1′-biphenyl]-3-yl)methoxy)-5-methoxy- 2,3-dihydro-1H-inden-4- yl)methyl)-4-hydroxypyrrolidine-2- carboxylic acid 58

  489.32 1.96-1.99 (m, 2H), 2.78 (m, 2H), 2.89 (m, 2H), 3.52 (bs, 7H),3.80 (s, 3H), 4.03 (m, 2H), 4.71 (bs, 2H), 5.36 (s, 2H), 6.65 (s, 1H),7.50-7.61 (m, 6H), 7.75-7.84 (m, 2H). 3-(((7-(((1,3-dihydroxy-2-(hydroxymethyl)propan-2- yl)amino)methyl)-6- methoxy-2,3-dihydro-1H-inden-4-yl)oxy)methyl)- [1,1′-biphenyl]-2- carbonitrile 59

  499.34 1.94-1.98 (m, 2H), 2.27 (m, 1H), 2.76 (m, 2H), 2.86 (m, 1H),2.98 (m, 2H), 3.10 (m, 1H), 3.46 (m, 1H), 3.55 (m, 1H), 3.61-3.68 (m,3H), 3.74 (m, 1H), 3.76 (s, 3H), 5.34 (s, 2H), 6.60 (s, 1H), 7.48-7.62(m, 6H), 7.77 (t, J = 7.2 Hz, 1H), 7.82 (t, J = 7.6 Hz, 1H).(S)-4-((7-((2-cyano[1,1′- biphenyl]-3-yl)methoxy)-5-methoxy-2,3-dihydro- 1H-inden-4- yl)methyl)morpholine-3- carboxylicacid 60

  443.44 1.95-1.99 (m, 2H), 2.78 (m, 2H), 2.92 (m, 2H), 3.09 (bs, 2H),3.84 (s, 3H), 3.93 (s, 2H), 5.39 (s, 2H), 6.69 (s, 1H), 7.50-7.62 (m,6H), 7.75- 7.84 (m, 2H). ((7-((2-cyano-[1,1′-biphenyl]-3-yl)methoxy)-5-methoxy- 2,3-dihydro-1H-inden-4- yl)methyl)glycine 61

  509.45 0.48 (m, 1H), 0.61 (m, 3H), 1.87 (m, 1H), 1.97- 2.01 (m, 2H),2.36 (m, 1H), 2.78 (m, 2H), 2.87- 3.03 (m, 5H), 3.85 (s, 3H), 4.18 (m,2H), 5.38 (s, 2H), 6.71 (s, 1H), 7.50-7.61 (m, 6H), 7.75- 7.84 (m, 2H).(S)-5-((7-((2-cyano-[1,1′- biphenyl]-3-yl)methoxy)-5-methoxy-2,3-dihydro- 1H-inden-4-yl)methyl)-5- azaspiro[2.4]heptane-6-carboxylic acid 62

  509.39 1.19 (m, 1H), 1.25 (m, 2H), 1.37 (m, 1H), 1.62 (m, 1H), 1.78(m, 2H), 1.97-2.01 (m, 2H), 2.21 (m, 1H), 2.30 (m, 1H), 2.66-2.78 (m,3H), 2.93- 3.03 (m, 1H), 3.48 (d, J = 12.4 Hz, 1H), 3.58 (d, J = 12.4Hz, 1H), 3.84 (s, 3H), 5.37 (s, 2H), 6.70 (s, 1H), 7.50-7.61 (m, 6H),7.75-7.84 (m, 2H). rac-(1R,6S)-2-((7-((2-cyano-[1,1′-biphenyl]-3-yl)methoxy)- 5-methoxy-2,3-dihydro-1H-inden-4-yl)methyl)-2- azabicyclo[4.1.0]heptane-1- carboxylic acid (cis,racemic) 63

  511.48 1.37 (m, 3H), 1.59 (m, 2H), 1.84 (m, 1H), 1.97- 2.01 (m, 2H),2.13-2.19 (m, 1H), 2.39 (m, 1H), 2.66 (m, 1H), 2.78 (m, 3H), 2.84-2.99(m, 3H), 3.66 (d, J = 12.8 Hz, 1H), 3.78 (s, 3H), 3.85 (m, 1H), 5.36 (s,2H), 6.64 (s, 1H), 7.50-7.61 (m, 6H), 7.75-7.84 (m, 2H).2-(1-((7-((2-cyano-[1,1′- biphenyl]-3-yl)methoxy)-5-methoxy-2,3-dihydro- 1H-inden-4- yl)methyl)piperidin-2- yl)acetic acid

Example-64 Synthesis ofN-(2-(((7-((2-cyano-[1,1′-biphenyl]-3-yl)methoxy)-5-methoxy-2,3-dihydro-1H-inden-4-yl)methyl)(methyl)amino)ethyl)-N-methylacetamide

Step-1: To a solution of3-(((7-formyl-6-methoxy-2,3-dihydro-1H-inden-4-yl)oxy)methyl)-[1,1′-biphenyl]-2-carbonitrile(250 mg, 0.65 mmol), N¹,N²-dimethylethane-1,2-diamine (115 mg, 1.30mmol), and acetic acid (2 drops) in DMF (3 mL)) and MeOH (3 mL), thereaction mixture was stirred at rt for 30 minutes. To this mixture,sodium cyanoborohydride (40 mg, 0.130 mmol) was added and stirred for 16h. After completion, the reaction mixture was poured on ice cold water(10 mL) and extracted with DCM (3×50 mL) and the organic layer was driedover sodium sulfate and concentrated. The resulting crude was purifiedby flash chromatography (silica gel, 4 g cartridge) using 0-20% MeOH inDCM as eluent to obtain3-(((6-methoxy-7-((methyl(2-(methylamino)ethyl)amino)methyl)-2,3-dihydro-1H-inden-4-yl)oxy)methyl)-[1,1′-biphenyl]-2-carbonitrile(Yield: 100 mg, 33%) as white solid. LCMS (ES) m/z=456.30 [M+H]⁺.

Step-2: To a stirred solution of3-(((6-methoxy-7-((methyl(2-(methylamino)ethyl)amino)methyl)-2,3-dihydro-1H-inden-4-yl)oxy)methyl)-[1,1′-biphenyl]-2-carbonitrile(80 mg, 0.176 mmol), AcOH (5 drops) in DMF (5 mL), HOBt (35 mg, 0.26mmol), EDC.HCl (50 mg, 0.26 mmol), N,N-diisopropylethylamine (68 mg,0.53 mmol) were added and stirred the mixture for 12 h at roomtemperature. After completion, diluted the mixture with water (10 mL)and extracted with 10% MeOH in DCM (3×20 mL). The organic layer wasdried and concentrated. The crude was purified by flash chromatography(silica gel, 4 g cartridge) using 0-10% MeOH in DCM as eluent to obtainN-(2-(((7-((2-cyano-[1,1′-biphenyl]-3-yl)methoxy)-5-methoxy-2,3-dihydro-1H-inden-4-yl)methyl)(methyl)amino)ethyl)-N-methylacetamide(Yield: 12 mg) as white solid. LCMS (ES) m/z=498.25 [M+H]⁺; ¹H NMR (400MHz, DMSO-d₆) δ ppm: 1.90-2.14 (m, 8H), 2.48 (m, 2H), 2.58 (m, 1H),2.77-2.86 (m, 6H), 3.32-3.37 (bs, 3H), 3.76 (s, 3H), 3.78 (m, 1H), 5.35(s, 2H), 6.68 (s, 1H), 7.50-7.61 (m, 6H), 7.75-7.84 (m, 3H).

Example-65 Synthesis of5-((4-(((2-acetamidoethyl)amino)methyl)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)pentanoicacid

Step-1: To a solution of5-hydroxy-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-indene-4-carbaldehyde(0.40 g, 1.12 mmol) in DMF (10 mL), potassium carbonate (0.46 g, 3.38mmol) and methyl 5-bromopentanoate (0.217 g, 1.22 mmol) was added andthe reaction mixture was stirred at 60° C. for 6 h. After completion,the reaction mixture was diluted with water (20 mL) and extracted withEtOAc (3×30 mL). The combined organic layer was dried over sodiumsulfate and concentrated. The resulting crude was purified by flashchromatography (silica gel, 12 g cartridge) using 20% EtOAc in hexanesas eluent to obtain methyl5-((4-formyl-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)pentanoate(Yield: 0.310 g, 58%) as white solid. LCMS (ES) m/z=473.50 [M+H]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ ppm: 1.71-1.81 (m, 4H), 1.99-2.00 (m, 2H), 2.22(s, 3H), 2.41 (m, 2H), 2.69 (m, 2H), 3.13 (m, 2H), 3.58 (s, 3H), 4.16(m, 2H), 5.32 (s, 2H), 6.78 (s, 1H), 7.22 (d, J=8.0 Hz, 1H), 7.28-7.40(m, 4H), 7.44-7.50 (m, 3H), 10.35 (s, 1H).

Step-2: To a solution of methyl5-((4-formyl-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)pentanoate(150 mg, 0.32 mmol), in MeOH (3 mL) and DMF (3 mL),N-(2-aminoethyl)acetamide (32.7 mg, 0.48 mmol) and acetic acid (3 drops)were added and stirred the reaction mixture for 10 minutes. To thismixture, sodium cyanoborohydride (57 mg, 0.935 mmol) was added and themixture was stirred at room temperature for 16 h. After completion, thereaction mixture was diluted with water (10 mL) and extracted with 10%MeOH in DCM (3×30 mL). The organic layer was dried over anhydrous sodiumsulphate and concentrated. The resulting crude was purified by flashchromatography (silica gel, 4 g cartridge) using 0-10% MeOH in DCM aseluent to obtain methyl5-((4-(((2-acetamidoethyl)amino)methyl)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)pentanoate(Yield: 80 mg, 45%) as white solid. LCMS (ES) m/z=559.55 [M+H]⁺; ¹H NMR(400 MHz, DMSO-d₆) δ ppm: 1.70-1.76 (m, 4H), 1.78 (s, 3H), 1.99-2.00 (m,2H), 2.33 (s, 3H), 2.39 (m, 2H), 2.57 (m, 2H), 2.75 (m, 2H), 2.88 (m,2H), 3.18 (m, 2H), 3.59 (s, 3H), 3.72 (m, 2H), 4.01 (m, 2H), 5.18 (s,2H), 6.70 (s, 1H), 7.22 (d, J=8.0 Hz, 1H), 7.28-7.40 (m, 4H), 7.44-7.48(m, 3H), 7.86 (bs, 1H).

Step-3: To a stirred solution of methyl5-((4-(((2-acetamidoethyl)amino)methyl)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)pentanoate(70 mg, 0.125 mmol) in THF (3 mL) and water (1.5 mL), lithium hydroxide(10.5 mg, 0.25 mmol) was added and stirred the mixture at roomtemperature for 16 h. After completion, the reaction mixture was dilutedwith water (5 mL) and acidified with 1N HCl. The aqueous mixture wasextracted with EtOAc (3×20 mL) and combined organic extract was driedover sodium sulphate and concentrated. The crude was purified by flashchromatography (silica gel, 4 g cartridge) using ammoniated solution of10% MeOH in DCM as eluent to obtain5-((4-(((2-acetamidoethyl)amino)methyl)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)pentanoicacid (Yield: 20 mg, 29%) as white solid. LCMS (ES) m/z=545.46 [M+H]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ ppm: 1.67-1.74 (m, 4H), 1.76 (s, 3H), 1.95-1.98(m, 2H), 2.21 (s, 3H), 2.28 (m, 2H), 2.55 (m, 2H), 2.74 (m, 2H), 2.85(m, 2H), 3.12 (m, 2H), 3.60 (s, 2H), 3.98 (m, 2H), 5.15 (s, 2H), 6.61(s, 1H), 7.18 (d, J=7.6 Hz, 1H), 7.26-7.39 (m, 4H), 7.44-7.48 (m, 3H),7.83 (bs, 1H).

Example-66 Synthesis of5-((4-(((2-acetamidoethyl)amino)methyl)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)pentanamide

Step-1: To a stirred solution of methyl5-((4-(((2-acetamidoethyl)amino)methyl)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)pentanoate(60 mg, 0.107 mmol) in MeOH (10 mL) at −60° C. in a steel bomb, ammoniagas was purged for 10 minutes, after sealing the steel bomb the mixturewas heated at 60° C. and stirred for 16 h. After completion, excessammonia was removed by flushing nitrogen gas and concentrated thereaction mixture. The crude was purified by flash chromatography (silicagel, 4 g cartridge) using 10% MeOH in DCM as eluent to obtain5-((4-(((2-acetamidoethyl)amino)methyl)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)pentanamide(Yield: 30 mg, 51%) as white solid. LCMS (ES) m/z=544.42 [M+H]⁺; ¹H NMR(400 MHz, DMSO-d₆) δ ppm: 1.67-1.74 (m, 4H), 1.76 (s, 3H), 1.95-1.98 (m,2H), 2.21 (s, 3H), 2.45 (m, 2H), 2.56 (m, 2H), 2.75 (m, 2H), 2.86 (m,2H), 3.12 (m, 2H), 3.63 (s, 2H), 3.98 (m, 2H), 5.16 (s, 2H), 6.62 (s,1H), 6.74 (bs, 1H), 7.19 (d, J=7.6 Hz, 1H), 7.26-7.39 (m, 5H), 7.44-7.48(m, 3H), 7.80 (bs, 1H).

Example-67 Synthesis of(S)-1-((5-(4-carboxybutoxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylicacid

Step-1: To a solution of methyl5-((4-formyl-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)pentanoate(340 mg, 0.71 mmol), in MeOH (4 mL) and DMF (4 mL),(S)-piperidine-2-carboxylic acid (102 mg, 0.79 mmol) and acetic acid (3drops) were added and stirred for 2 h. To this mixture, sodiumcyanoborohydride (134 mg, 2.1 mmol) was added and the mixture wasstirred at room temperature for 16 h. After completion, the reactionmixture was diluted with water (10 mL) and extracted with 10% MeOH inDCM (3×30 mL). The organic layer was dried over anhydrous sodiumsulphate and concentrated. The resulting crude was purified by flashchromatography (silica gel, 4 g cartridge) using 0-10% MeOH in DCM aseluent to obtain(S)-1-((5-((5-methoxy-5-oxopentyl)oxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylicacid (Yield: 245 mg, 59%) as light yellow solid. LCMS (ES) m/z=584.63[M−H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 1.45 (m, 4H), 1.74 (m, 7H),1.96-2.00 (m, 2H), 2.21 (s, 3H), 2.39 (m, 2H), 2.75 (m, 2H), 2.80 (m,1H), 2.95 (m, 1H), 3.05 (m, 1H), 3.11 (m, 1H), 3.59 (s, 3H), 3.75 (d,J=12.0 Hz, 1H), 3.88 (d, J=12.0 Hz, 1H), 4.00 (m, 2H), 5.20 (s, 2H),6.64 (s, 1H), 7.19 (d, J=7.6 Hz, 1H), 7.27-7.40 (m, 4H), 7.44-7.49 (m,3H).

Step-2: To a stirred solution of(S)-1-((5-((5-methoxy-5-oxopentyl)oxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylicacid (70 mg, 0.11 mmol) in THF (3 mL) and water (1.5 mL), lithiumhydroxide (10.5 mg, 0.23 mmol) was added and stirred the mixture at roomtemperature for 16 h. After completion, the reaction mixture was dilutedwith water (10 mL) and acidified with 1N HCl. The aqueous mixture wasextracted with EtOAc (3×20 mL) and combined organic extract was driedover sodium sulphate and concentrated. The crude was purified by flashchromatography (silica gel, 4 g cartridge) using ammoniated solution of10% MeOH in DCM as eluent to obtain(S)-1-((5-(4-carboxybutoxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylicacid (Yield: 38 mg, 61%) as white solid. LCMS (ES) m/z=572.39 [M+H]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ ppm: 1.38-1.49 (m, 4H), 1.74 (m, 6H), 1.95-1.98(m, 2H), 2.21 (s, 3H), 2.26 (m, 2H), 2.73 (m, 2H), 2.81 (m, 1H), 3.03(m, 2H), 3.12 (m, 2H), 3.84 (s, 2H), 3.98 (m, 2H), 5.16 (s, 2H), 6.63(s, 1H), 7.18 (d, J=7.6 Hz, 1H), 7.26-7.39 (m, 4H), 7.44-7.49 (m, 3H).

Example-68 Synthesis of(S)-1-((5-((5-amino-5-oxopentyl)oxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylicacid

Step-1: To a stirred solution of(S)-1-((5-((5-methoxy-5-oxopentyl)oxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylicacid (103 mg, 0.18 mmol) in MeOH (10 mL) at −35° C. in a steel bomb,ammonia gas was purged for 5 minutes. After sealing the steel bomb, themixture was heated at 55° C. and stirred for 36 h. After completion,excess ammonia was removed by flushing nitrogen gas and concentrated thereaction mixture. The crude was purified by flash chromatography (silicagel, 4 g cartridge) using 8% MeOH in DCM as eluent to obtain(S)-1-((5-((5-amino-5-oxopentyl)oxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylicacid (Yield: 60 mg, 60%) as off-white solid. LCMS (ES) m/z=571.45[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 1.43-1.74 (m, 5H), 1.74 (m,4H), 1.95-1.98 (m, 3H), 2.11-2.13 (m, 2H), 2.21 (s, 3H), 2.73 (m, 2H),2.83 (m, 1H), 3.05 (m, 2H), 3.50 (m, 2H), 3.96-4.03 (m, 4H), 5.19 (s,2H), 6.67 (s, 1H), 6.75 (bs, 1H), 7.20 (d, J=7.6 Hz, 1H), 7.26-7.39 (m,5H), 7.44-7.49 (m, 3H).

Example-69 Synthesis of(S)-1-((5-((5-cyanopyridin-3-yl)methoxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylic acid

Step-1: To a solution of5,7-dihydroxy-2,3-dihydro-1H-indene-4-carbaldehyde (0.34 g, 1.92 mmol)in acetonitrile (20 mL), potassium carbonate (0.31 g, 2.30 mmol) and3-(bromomethyl)-[1,1′-biphenyl]-2-carbonitrile (0.50 g, 1.92 mmol) wereadded. The reaction mixture was stirred at room temperature for 16 h.After completion, the reaction mixture was diluted with water (20 mL)and extracted with EtOAc (3×20 mL). The combined organic layer was driedover sodium sulfate and concentrated. The resulting crude was purifiedby flash chromatography (silica gel, 4 g cartridge) using 0-20% EtOAc inhexane as eluent to obtain3-(((7-formyl-6-hydroxy-2,3-dihydro-1H-inden-4-yl)oxy)methyl)-[1,1′-biphenyl]-2-carbonitrile(Yield: 0.50 g, 71%) as yellow solid. LCMS (ES) m/z=370.45 [M+H]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ ppm: 2.04 (m, 2H), 2.73 (t, J=7.2 Hz, 2H), 3.14(t, J=7.6 Hz, 2H), 5.41 (s, 2H), 6.53 (s, 1H), 7.51-7.63 (m, 6H), 7.75(m, 1H), 7.83 (m, 1H), 10.08 (s, 1H), 11.22 (s, 1H).

Step-2: To a solution of3-(((7-formyl-6-hydroxy-2,3-dihydro-1H-inden-4-yl)oxy)methyl)-[1,1′-biphenyl]-2-carbonitrile(0.75 g, 2.03 mmol) in DMF (15 mL), potassium carbonate (0.82 g, 6.09mmol) and 5-(chloromethyl)nicotinonitrile (0.92 g, 6.09 mmol) was addedand stirred the mixture at room temperature for 16 h. After completion,the reaction mixture was diluted with ice cold water (30 mL) andextracted with EtOAc (3×50 mL). The combined organic layer was driedover sodium sulfate and concentrated. The resulting crude was purifiedby column chromatography (silica gel, 100-200 mesh) using 0-50% EtOAc inhexane as eluent to obtain5-(((7-((2-cyano-[1,1′-biphenyl]-3-yl)methoxy)-4-formyl-2,3-dihydro-1H-inden-5-yl)oxy)methyl)nicotinonitrile(Yield: 0.55 g, 57%) as off-white solid. LCMS (ES) m/z=486.50 [M+H]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ ppm: 1.99-2.02 (m, 2H), 2.73 (m, 2H), 3.14 (m,2H), 5.42 (s, 2H), 5.49 (s, 2H), 6.94 (s, 1H), 7.51-7.64 (m, 6H), 7.74(m, 1H), 7.82 (m, 1H), 8.51 (s, 1H), 9.01 (d, J=5.2 Hz, 2H), 10.38 (s,1H).

Step-3: To a solution of5-(((7-((2-cyano-[1,1′-biphenyl]-3-yl)methoxy)-4-formyl-2,3-dihydro-1H-inden-5-yl)oxy)methyl)nicotinonitrile(180 mg, 0.37 mmol), (S)-piperidine-2-carboxylic acid (40 mg, 0.33 mmol)in DMF (2 mL) and MeOH (2 mL), acetic acid (2 drops) was added andstirred the mixture for 2 h. To this mixture, sodium cyanoborohydride(68 mg, 1.11 mmol) and) was added and continued stirring at roomtemperature for 16 h. After completion, the reaction mixture was pouredon ice cold water (10 mL) and extracted with 5% MeOH in DCM (3×10 mL).The combined organic layer was dried over sodium sulfate andconcentrated. The resulting crude was purified by column chromatography(silica gel, 100-200 mesh) using 0-20% MeOH in DCM as eluent to obtain(S)-1-((7-((2-cyano-[1,1′-biphenyl]-3-yl)methoxy)-5-((5-cyanopyridin-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylicacid (Yield: 30 mg, 14%) as white solid. LCMS (ES) m/z=599.55 [M+H]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ ppm: 1.33-1.46 (m, 4H), 1.74 (m, 2H), 1.93-2.00(m, 2H), 2.30 (m, 1H), 2.81 (m, 2H), 2.82-3.08 (m, 4H), 3.62 (d, J=12.4Hz, 1H), 3.86 (d, J=12.4 Hz, 1H), 5.28 (s, 2H), 5.33 (m, 2H), 6.76 (s,11H), 7.50-7.61 (m, 6H), 7.72 (d, J=7.2 Hz, 11H), 7.79 (t, J=7.6 Hz,11H), 8.47 (s, 11H), 8.98 (s, 11H), 9.00 (s, 11H).

Following compounds were prepared by following similar to aboveprocedures

TABLE 4 LCMS m/z ¹H NMR (400 MHz, S. No. Structure [M + H]⁺ DMSO-d₆) δppm 70

  601.50. 1.96-2.09 (m, 4H), 2.73- 2.78 (m, 3H), 2.87-3.05 (m, 2H), 3.27(bs, 1H), 3.66 (m, 1H), 4.16 (m, 2H), 4.23 (m, 1H), 5.19 (s, 1H), 5.29(s, 2H), 5.35 (m, 2H), 6.81 (s, 1H), 7.51-7.62 (m, 6H), 7.72 (d, J = 7.2Hz, 1H), 7.79 (t, J = 7.6 Hz, 1H), 8.51 (s, 1H), 8.99 (s, 1H), 9.01 (s,1H). (2S,4R)-1-((7-((2-cyano- [1,1′-biphenyl]-3- yl)methoxy)-5-((5-cyanopyridin-3- yl)methoxy)-2,3-dihydro- 1H-inden-4-yl)methyl)-4-hydroxypyrrolidine-2- carboxylic acid 71

  599.45. 1.33-1.42 (m, 2H), 1.58 (m, 1H), 1.76 (m, 1H), 1.96-2.01 (m,2H), 2.10 (m, 1H), 2.20 (m, 1H), 2.33 (m, 1H), 2.56 (m, 1H), 2.78 (m,3H), 2.88 (m, 2H), 3.42 (s, 2H), 5.26 (s, 2H), 5.33 (m, 2H), 6.76 (s,1H), 7.49- 7.61 (m, 6H), 7.72 (d, J = 7.2 Hz, 1H), 7.80 (t, J = 7.6 Hz,1H), 8.38 (s, 1H), 8.98 (s, 1H), 8.99 (s, 1H).(R)-1-((7-((2-cyano-[1,1′- biphenyl]-3-yl)methoxy)-5((5-cyanopyridin-3-yl)methoxy)- 2,3 -dihydro-1H-inden-4-yl)methyl)piperidine-3- carboxylic acid 72

  611.48 [M + H]⁺; 1.13-1.33 (m, 4H), 1.56 (m, 1H), 1.66 (m, 1H), 1.76(m, 1H), 1.96-1.99 (m, 2H), 2.32-2.38 (m, 2H), 2.75-2.82 (m, 3H),2.99-3.03 (m, 1H), 3.66 (m, 2H), 5.31 (s, 2H), 5.33 (m, 2H), 6.77 (s,1H), 7.50-7.61 (m, 6H), 7.69 (d, J = 7.2 Hz, 1H), 7.79 (t, J = 7.6 Hz,1H), 8.39 (s, 1H), 8.94 (s, 1H), 8.99 (s, 1H).rac-(1R,6S)-2-((7-((2-cyano- [1,1′-biphenyl]-3-yl)methoxy)-5-((5-cyanopyridin-3- yl)methoxy)-2,3-dihydro-1H- inden-4-yl)methyl)-2-azabicyclo[4.1.0]heptane-1- carboxylic acid (cis; racemic) 73

  641.39. 0.95 (m, 1H), 1.52 (m, 6H), 1.75 (m, 6H), 1.97 (m, 2H), 2.20(s, 3H), 2.74 (m, 2H), 2.85 (m, 2H), 3.50-3.56 (m, 5H), 5.14-5.18 (m,4H), 6.72 (s, 1H), 7.19 (d, J = 7.2 Hz, 1H), 7.24-7.32 (m, 3H), 7.39 (m,1H), 7.43- 7.47 (m, 3H), 7.61 (t, J = 8.56 Hz, 1H), 7.81 (m, 2H), 8.02(s, 1H). methyl 4-(((5-((3- cyanobenzyl)oxy)-7-((2-methyl-[1,1′-biphenyl]-3- yl)methoxy)-2,3-dihydro-1H- inden-4-yl)methyl)amino)bicyclo[2.2.2] octane-1-carboxylate

Example-74 Synthesis of4-(((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid

Step-1: To a solution of methyl4-(((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylate (160 mg, 0.24 mmol) in THF (6 mL) andwater (4 mL), lithium hydroxide (83 mg, 1.99 mmol) was added and stirredthe mixture at room temperature for 12 h. After completion, the reactionmixture was diluted with water (20 mL) and extracted with EtOAc (30 mL).The aqueous layer was acidified to pH 4 using 3N HCl solution and thereaction mixture was extracted with 10% MeOH in DCM (2×100 mL). Thecombined organic layer was dried over sodium sulfate and concentrated.The resulting crude was purified by flash chromatography (silica gel, 4g cartridge) using 0-10% MeOH in DCM as eluent to obtain4-(((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid (Yield: 50 mg, 32%) as white solid. LCMS (ES) m/z=627.37 [M+H]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ ppm: 1.73 (m, 12H), 2.00 (m, 2H), 2.20 (s, 3H),2.77 (m, 2H), 3.02 (m, 2H), 3.86 (m, 2H), 5.20-5.22 (m, 4H), 6.82 (s,1H), 7.19 (d, J=7.2 Hz, 1H), 7.24-7.32 (m, 3H), 7.39 (m, 1H), 7.43-7.47(m, 3H), 7.66 (t, J=8.56 Hz, 1H), 7.87 (m, 2H), 8.02 (s, 1H), 8.43 (bs,1H), 12.14 (bs, 1H).

Example-75 Synthesis of(S)-1-((5-methoxy-7-((2-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylicacid

Step-1: To a solution of7-hydroxy-5-methoxy-2,3-dihydro-1H-indene-4-carbaldehyde (0.50 g, 1.5mmol) and 3-(bromomethyl)-2-(trifluoromethyl)-1,1′-biphenyl (0.29 g, 1.5mmol) in ACN (10 mL), potassium carbonate (0.31 g, 2.25 mmol) was addedand stirred the mixture at room temperature for 16 h. After completion,the reaction mixture was diluted with water (20 mL) and extracted withEtOAc (3×40 mL). The organic layer was dried over sodium sulphate andconcentrated. The crude was purified by flash chromatography (silicagel, 12 g cartridge) using 0-30% EtOAc in hexanes as eluent to obtain5-methoxy-7-((2-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-indene-4-carbaldehyde(Yield: 0.3 g, 47%) as off-white solid. LCMS (ES) m/z=427.45 [M+H]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ ppm: 1.98-2.04 (m, 2H), 2.70 (m, 2H), 3.12 (m,2H), 3.91 (s, 3H), 5.47 (s, 2H), 6.69 (s, 1H), 7.30 (d, J=6.0 Hz, 2H),7.37-7.46 (m, 4H), 7.73 (t, J=7.6 Hz, 1H), 7.79 (d, J=7.6 Hz, 1H), 10.31(s, 1H).

Step-2: To a stirred solution of5-methoxy-7-((2-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-indene-4-carbaldehyde(0.10 g, 0.23 mmol), (S)-piperidine-2-carboxylic acid (27 mg, 0.21 mmol)in DMF (1 mL) and MeOH (1 mL), acetic acid (2 drops) was added andcontinued stirring of the mixture for 1 h. To this mixture, sodiumcyanoborohydride (40 mg, 0.69 mmol) and) was added and continuedstirring at room temperature for 16 h and the mixture was heated at 50°C. for 5 h. After completion, the reaction mixture was poured on icecold water (10 mL) and extracted with 10% MeOH in DCM (3×10 mL). Thecombined organic layer was dried over sodium sulfate and concentrated.The resulting crude was purified by flash chromatography (silica gel, 4g cartridge) using 0-10% MeOH in DCM as eluent to obtain(S)-1-((5-methoxy-7-((2-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylicacid (Yield: 30 mg, 25%) as white solid. LCMS (ES) m/z=540.36 [M+H]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ ppm: 1.33-1.46 (m, 4H), 1.77 (m, 2H), 1.97-2.00(m, 2H), 2.42 (m, 1H), 2.76 (m, 2H), 2.84 (m, 1H), 2.91 (m, 1H),3.02-3.09 (m, 1H), 3.14 (m, 1H), 3.73-3.76 (m, 4H), 3.88 (d, J=12.4 Hz,1H), 5.34 (s, 2H), 6.54 (s, 1H), 7.30 (d, J=6.4 Hz, 2H), 7.35 (d, J=7.6Hz, 1H), 7.41-7.46 (m, 3H), 7.71 (t, J=7.6 Hz, 1H), 7.79 (d, J=7.6 Hz,1H).

Following compounds were prepared by following similar to aboveprocedures

Example 76(2S,4R)-4-hydroxy-1-((5-methoxy-7-((2-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-ylmethyl)pyrrolidine-2-carboxylicacid

LCMS (ES) m/z=542.41 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 1.95-1.99(m, 3H), 2.09 (m, 1H), 2.26-2.79 (m, 3H), 2.86-3.02 (m, 2H), 3.25 (m,1H), 3.66 (m, 1H), 3.81 (s, 3H), 4.05-4.12 (m, 2H), 4.23 (bs, 1H), 5.26(bs, 1H), 5.36 (s, 2H), 6.59 (s, 1H), 7.30 (d, J=6.4 Hz, 2H), 7.35 (d,J=7.6 Hz, 1H), 7.41-7.46 (m, 3H), 7.71 (t, J=7.6 Hz, 1H), 7.79 (d, J=7.6Hz, 1H).

Example-77 Synthesis of(2S)-1-((7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-5-((1-methylpiperidin-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylicacid

Step-1: To a stirred solution of 1-methyl-3-hydroxymethylpiperidine (2g, 15.5 mmol) in DCM (30 mL) at 0° C., triethylamine (4.9 g, 46 mmol)and tosyl chloride (4.41 g, 23.2 mmol) were added and allowed themixture to stir at room temperature for 6 h. After completion, thereaction mixture was diluted with water (30 mL) and extracted with DCM(3×30 mL). The combined organic layer was dried over sodium sulfate andconcentrated. The resulting crude was purified by flash chromatography(silica gel, 12 g cartridge) using 0-20% EtOAc in hexanes as eluent toobtain (1-methylpiperidin-3-yl)methyl 4-methylbenzenesulfonate (Yield:2.50 g, 58%) as white solid. LCMS (ES) m/z=284.36 [M+H]⁺; ¹H NMR (400MHz, DMSO-d₆) δ ppm: 0.87-0.95 (m, 1H), 1.33-1.50 (m, 4H), 1.63 (m, 1H),1.80-1.85 (m, 2H), 2.06 (s, 3H), 2.42 (s, 3H), 2.46-2.52 (m, 1H), 3.90(m, 2H), 7.48 (d, J=8.0 Hz, 2H). 7.78 (d, J=8.0 Hz, 2H).

Step-2: To a solution of5-hydroxy-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-indene-4-carbaldehyde(200 mg, 0.558 mmol) in DMF (5 mL), potassium carbonate (231 mg, 1.67mmol) and (1-methylpiperidin-3-yl)methyl 4-methylbenzenesulfonate (238mg, 0.84 mmol) were added and stirred the reaction mixture at roomtemperature for 16 h. After completion, the reaction mixture was dilutedwith ice cold water (15 mL) and extracted with 5% MeOH in DCM (3×20 mL).The combined organic layer was dried over sodium sulfate andconcentrated. The resulting crude was purified by column chromatography(silica gel, 100-200 mesh) using 0-10% MeOH in DCM as eluent to obtain7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-5-((1-methylpiperidin-3-yl)methoxy)-2,3-dihydro-1H-indene-4-carbaldehyde(Yield: 0.15 g, 57%) as white solid. LCMS (ES) m/z=470.54 [M+H]⁺;

Step-3: A solution of7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-5-((1-methylpiperidin-3-yl)methoxy)-2,3-dihydro-1H-indene-4-carbaldehyde(150 mg, 0.319 mmol), (S)-piperidine-2-carboxylic acid (123 mg, 0.96mmol) in DMF (2.5 mL) and MeOH (2.5 mL), acetic acid (3 drops) wereadded and stirred the mixture for 1 h. To this mixture, sodiumcyanoborohydride (60 mg, 0.96 mmol) and) was added and continuedstirring at room temperature for 16 h. After completion, the reactionmixture was poured on ice cold water (10 mL) and extracted with 10% MeOHin DCM (3×20 mL). The combined organic layer was dried over sodiumsulfate and concentrated. The resulting crude was purified by columnchromatography (silica gel, 100-200 mesh) using 0-10% MeOH in DCM aseluent to obtain(2S)-1-((7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-5-((1-methylpiperidin-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylicacid (Yield: 18 mg, 9.6%) as white solid. LCMS (ES) m/z=583.57 [M+H]⁺;¹H NMR (400 MHz, DMSO-d₆) δ ppm: 1.47 (m, 5H), 1.64 (m, 4H), 1.74 (m,2H), 1.98-2.04 (m, 4H), 2.21 (s, 6H), 2.74 (m, 2H), 2.82 (m, 3H),2.98-3.04 (m, 3H), 3.15 (m, 1H), 3.72 (d, J=12.4 Hz, 1H), 3.89 (m, 3H),5.17 (s, 2H), 6.61 (s, 1H), 7.19 (d, J=7.2 Hz, 1H), 7.26-7.32 (m, 3H),7.38 (t, J=7.2 Hz, 1H), 7.44-7.48 (m, 3H).

Example-78 Synthesis of(S)-1-((5-(4-carboxybutoxy)-7-((2-cyano-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylicacid

Step-1: To a solution of3-(((7-formyl-6-hydroxy-2,3-dihydro-1H-inden-4-yl)oxy)methyl)-[1,1′-biphenyl]-2-carbonitrile(0.25 g, 0.697 mmol) in ACN (10 mL), potassium carbonate (0.280 g, 2.03mmol) and methyl 5-bromopentanoate (0.396 g, 2.03 mmol) were added andstirred the mixture at room temperature for 16 h. After completion, thereaction mixture was diluted with water (20 mL) and extracted with EtOAc(3×30 mL). The combined organic layer was dried over sodium sulfate andconcentrated. The resulting crude was purified by flash chromatography(silica gel, 12 g cartridge) using 30% EtOAc in hexanes as eluent toobtain methyl5-((7-((2-cyano-[1,1′-biphenyl]-3-yl)methoxy)-4-formyl-2,3-dihydro-1H-inden-5-yl)oxy)pentanoate(Yield: 0.150 g, 45%) as white solid. LCMS (ES) m/z=484.26 [M+H]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ ppm: 1.69-1.80 (m, 4H), 1.95-2.02 (m, 2H), 2.40(m, 2H), 2.69 (m, 2H), 3.13 (m, 2H), 3.58 (s, 3H), 4.16 (m, 2H), 5.48(s, 2H), 6.78 (s, 1H), 7.49-7.58 (m, 6H), 7.75 (m, 1H), 7.83 (m, 1H),10.33 (s, 1H).

Step-2: A solution of methyl5-((7-((2-cyano-[1,1′-biphenyl]-3-yl)methoxy)-4-formyl-2,3-dihydro-1H-inden-5-yl)oxy)pentanoate(220 mg, 0.46 mmol), (S)-piperidine-2-carboxylic acid (176 mg, 1.366mmol) in DMF (2 mL) and MeOH (2 mL), acetic acid (6 drops) was stirredfor 30 minutes. To this mixture, sodium cyanoborohydride (86 mg, 1.366mmol) and) were added and continued stirring at room temperature for 16h. After completion, the reaction mixture was poured on ice cold water(10 mL) and extracted with DCM (3×15 mL). The combined organic layer wasdried over sodium sulfate and concentrated. The resulting crude waspurified by column chromatography (silica gel, 100-200 mesh) using 0-10%MeOH in DCM as eluent to obtain(S)-1-((7-((2-cyano-[1,1′-biphenyl]-3-yl)methoxy)-5-((5-methoxy-5-oxopentyl)oxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylicacid (Yield: 80 mg, 29%) as white solid. LCMS (ES) m/z=597.68 [M+H]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ ppm: 1.33-1.46 (m, 4H), 1.69-1.80 (m, 5H),1.95-2.02 (m, 2H), 2.45 (m, 2H), 2.78 (m, 2H), 2.82-3.08 (m, 4H), 3.12(m, 2H), 3.58 (s, 3H), 3.71 (d, J=12.4 Hz, 1H), 3.86 (d, J=12.8 Hz, 1H),3.98 (m, 2H), 5.34 (m, 2H), 6.62 (s, 1H), 7.50-7.62 (m, 6H), 7.75 (m,1H), 7.83 (m, 1H).

Step-3: To a stirred solution of(S)-1-((7-((2-cyano-[1,1′-biphenyl]-3-yl)methoxy)-5-((5-methoxy-5-oxopentyl)oxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylicacid (70 mg, 0.117 mmol) in THF (3 mL) and water (1.5 mL), lithiumhydroxide (9.8 mg, 0.23 mmol) was added and stirred the mixture at roomtemperature for 16 h. After completion, the reaction mixture was dilutedwith water (10 mL) and acidified with 1N HCl. The aqueous mixture wasextracted with EtOAc (3×20 mL) and combined organic extract was driedover sodium sulphate and concentrated. The crude was purified by flashchromatography (silica gel, 4 g cartridge) using 0-15% MeOH in DCM aseluent to obtain(S)-1-((5-(4-carboxybutoxy)-7-((2-cyano-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylicacid (Yield: 15 mg, 22%) as white solid. LCMS (ES) m/z=583.48 [M+H]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ ppm: 1.38-1.49 (m, 4H), 1.76 (m, 6H), 1.95-1.98(m, 2H), 2.29 (m, 2H), 2.73 (m, 2H), 2.81 (m, 1H), 3.03 (m, 3H), 3.15(m, 1H), 3.78 (d, J=12.4 Hz, 1H), 3.90 (d, J=12.8 Hz, 1H), 3.99 (m, 2H),5.35 (s, 2H), 6.63 (s, 1H), 7.50-7.62 (m, 6H), 7.75 (m, 1H), 7.83 (m,1H).

Example-79 Synthesis ofN-(2-(((5-(4-cyanobutoxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)amino)ethyl)acetamide

Step-1: To a solution of5-hydroxy-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-indene-4-carbaldehyde(0.50 g, 1.39 mmol) in DMF (10 mL), potassium carbonate (0.288 g, 2.08mmol) and 5-bromopentanenitrile (0.25 g, 1.53 mmol) were added andstirred the mixture at room temperature for 5 h. After completion, thereaction mixture was diluted with water (20 mL) and extracted with EtOAc(3×30 mL). The combined organic layer was dried over sodium sulfate andconcentrated. The resulting crude was purified by flash chromatography(silica gel, 12 g cartridge) using 20% EtOAc in hexanes as eluent toobtain5-((4-formyl-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)pentanenitrile(Yield: 0.425 g, 69%) as white solid. LCMS (ES) m/z=440.51 [M+H]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ ppm: 1.74-1.80 (m, 2H), 1.86-1.90 (m, 2H),1.97-2.01 (m, 2H), 2.21 (s, 3H), 2.59 (m, 2H), 2.69 (m, 2H), 3.11 (m,2H), 4.20 (m, 2H), 5.31 (s, 2H), 6.79 (s, 1H), 7.22 (d, J=7.6 Hz, 1H),7.28-7.40 (m, 4H), 7.44-7.48 (m, 3H), 10.34 (s, 1H).

Step-2: To a solution of5-((4-formyl-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)pentanenitrile(150 mg, 0.35 mmol) in DMF (10 mL), N-(2-aminoethyl)acetamide (45 mg,0.44 mmol) and acetic acid (2 drops) were added and stirred the mixturefor 10 minutes. To this mixture, sodium cyanoborohydride (32 mg, 0.52mmol) was added and the mixture was stirred at room temperature for 6 h.After completion, the reaction mixture was diluted with water (15 mL)and extracted with 10% MeOH in DCM (3×30 mL). The organic layer wasdried over anhydrous sodium sulphate and concentrated. The resultingcrude was purified by flash chromatography (silica gel, 4 g cartridge)using 0-10% MeOH in DCM as eluent. The resulting product was furtherpurified by reverse phase HPLC using Method-E to obtainN-(2-(((5-(4-cyanobutoxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)amino)ethyl)acetamide(Yield: 40 mg) as sticky liquid. LCMS (ES) m/z=526.50 [M+H]⁺; ¹H NMR(400 MHz, DMSO-d₆) δ ppm: 1.78-1.82 (m, 5H), 1.84 (m, 2H), 1.97-1.99 (m,2H), 2.21 (s, 3H), 2.50 (m, 2H), 2.59 (m, 2H), 2.73 (m, 2H), 2.86 (m,2H), 3.11 (m, 2H), 3.60 (m, 2H), 4.02 (m, 2H), 5.15 (s, 2H), 6.63 (s,1H), 7.19 (d, J=7.6 Hz, 1H), 7.26-7.40 (m, 4H), 7.44-7.48 (m, 3H), 7.76(bs, 1H).

The following compounds were prepared following procedures describedabove

Example 80

(S)-1-((5-(4-cyanobutoxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxamide,LCMS (ES) m/z=552.52 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 1.47 (m,1H), 1.58 (m, 2H), 1.72-1.79 (m, 6H), 1.93-1.97 (m, 3H), 2.21 (s, 3H),2.59 (m, 3H), 2.66-2.83 (m, 5H), 2.94-3.02 (m, 1H), 3.15 (d, J=12.0 Hz,1H), 3.63 (d, J=12.0 Hz, 1H), 4.02 (m, 2H), 5.15 (s, 2H), 6.62 (s, 1H),7.06 (bd, 2H), 7.19 (d, J=7.6 Hz, 1H), 7.27-7.40 (m, 4H), 7.44-7.49 (m,3H).

Example 81

(2S,4R)-1-((5-(4-cyanobutoxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy-2,3-dihydro-1H-inden-4-yl)methyl)-4-hydroxypyrrolidine-2-carboxylicacid, LCMS (ES) m/z=551.51 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm:1.78-1.81 (m, 2H), 1.84-1.90 (m, 2H), 1.96-2.05 (m, 3H), 2.13 (m, 1H),2.22 (s, 3H), 2.59 (t, J=7.2 Hz, 2H), 2.74-2.81 (m, 3H), 2.88-2.98 (m,2H), 3.27 (m, 1H), 3.70 (t, J=8.0 Hz, 1H), 4.03-4.18 (m, 4H), 4.25 (m,1H), 5.19 (s, 2H), 5.29 (bs, 1H), 6.70 (s, 1H), 7.19 (d, J=7.6 Hz, 1H),7.27-7.40 (m, 4H), 7.44-7.49 (m, 3H).

Example-82 Synthesis of(S)-1-((5-(((1S,2R)-2-carboxycyclopropyl)methoxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylicacid

Step-1: To a solution of5-hydroxy-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-indene-4-carbaldehyde(0.20 g, 0.55 mmol) in DMF (4 mL), potassium carbonate (0.227 g, 1.6mmol) and methyl (1R,2S)-2-((tosyloxy)methyl)cyclopropane-1-carboxylate(0.321 g, 1.39 mmol) was added and stirred the mixture at roomtemperature for 12 h. After completion, the reaction mixture was dilutedwith water (6 mL) and extracted with EtOAc (3×10 mL). The combinedorganic layer was dried over sodium sulfate and concentrated. Theresulting crude was purified by flash chromatography (silica gel, 4 gcartridge) using 20% EtOAc in hexanes as eluent to obtain methyl(1R,2S)-2-(((4-formyl-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)cyclopropane-1-carboxylate(Yield: 0.330 g, crude) as yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δppm: 0.85 (m, 1H), 1.07 (m, 1H), 1.66 (m, 1H), 1.74-1.80 (m, 2H),1.86-1.90 (m, 2H), 1.97-2.01 (m, 2H), 2.21 (s, 3H), 2.71 (m, 2H), 3.10(m, 1H), 3.53 (s, 3H), 5.31 (s, 2H), 6.78 (s, 1H), 7.22 (d, J=7.6 Hz,1H), 7.28-7.40 (m, 4H), 7.44-7.48 (m, 3H), 10.24 (s, 1H).

Step-2: To a solution of methyl(1R,2S)-2-(((4-formyl-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)cyclopropane-1-carboxylate(150 mg, 0.32 mmol) in DMF (2 mL) and MeOH (2 mL),(S)-piperidine-2-carboxylic acid (61 mg, 0.48 mmol) and acetic acid (2drops) were added and stirred the mixture for 30 minutes. To thismixture, sodium cyanoborohydride (60 mg, 0.95 mmol) was added and themixture was stirred at 60° C. for 4 h. After completion, the reactionmixture was diluted with water (15 mL) and extracted with 10% MeOH inDCM (3×30 mL). The organic layer was dried over anhydrous sodiumsulphate and concentrated. The resulting crude was purified by flashchromatography (silica gel, 4 g cartridge) using 0-12% MeOH in DCM aseluent to obtain(S)-1-((5-(((1S,2R)-2-(methoxycarbonyl)cyclopropyl)methoxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylicacid (Yield: 180 mg) as off-white solid. LCMS (ES) m/z=584.59 [M+H]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ ppm: 0.95 (m, 1H), 1.03 (m, 1H), 1.39 (m, 1H),1.43-1.54 (m, 5H), 1.78-1.90 (m, 4H), 1.97-1.99 (m, 2H), 2.21 (s, 3H),2.72 (m, 2H), 2.84 (m, 2H), 3.03 (m, 2H), 3.51 (s, 3H), 3.79 (m, 1H),3.92 (m, 1H), 4.34 (m, 1H), 5.16 (s, 2H), 6.59 (s, 1H), 7.19 (d, J=7.6Hz, 1H), 7.26-7.40 (m, 4H), 7.44-7.48 (m, 3H).

Step-3: To a stirred solution of(S)-1-((5-(((1S,2R)-2-(methoxycarbonyl)cyclopropyl)methoxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylicacid (100 mg, 0.17 mmol) in THF (3 mL) and water (1.5 mL), lithiumhydroxide (14 mg, 0.35 mmol) was added and stirred the mixture at roomtemperature for 6 h. After completion, the reaction mixture was dilutedwith water (5 mL) and acidified with 1N HCl (pH 5-6). The aqueousmixture was extracted with 10% MeOH in DCM (3×10 mL) and combinedorganic extract was dried over sodium sulphate and concentrated. Thecrude was purified by column chromatography (silica gel, 100-200 mesh)using 0-30% MeOH in DCM as eluent. The resulting product was furtherpurified by reverse phase column chromatography to obtain(S)-1-((5-(((1S,2R)-2-carboxycyclopropyl)methoxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylicacid (Yield: 45 mg, 46%) as off-white solid. LCMS (ES) m/z=570.57[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 0.95 (m, 1H), 1.07 (m, 1H),1.39 (m, 1H), 1.43-1.54 (m, 3H), 1.78-1.90 (m, 4H), 1.97-1.99 (m, 2H),2.21 (s, 3H), 2.72 (m, 2H), 2.84 (m, 2H), 3.03 (m, 3H), 3.79 (m, 1H),3.97 (m, 2H), 4.39 (s, 1H), 5.17 (s, 2H), 6.65 (s, 1H), 7.19 (d, J=7.6Hz, 1H), 7.26-7.40 (m, 4H), 7.44-7.48 (m, 3H).

The following compounds were prepared following procedures describedabove

Example 83

(1R,2S)-2-(((4-(((2-acetamidoethyl)amino)methyl)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)cyclopropane-1-carboxylicacid, LCMS (ES) m/z=543.54 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 0.95(m, 2H), 1.67 (m, 2H), 1.78 (s, 3H), 1.97-2.00 (m, 2H), 2.20 (s, 3H),2.73 (m, 2H), 2.88 (m, 4H), 3.26-3.32 (m, 2H), 3.73 (m, 1H), 3.89 (m,1H), 3.95 (d, J=12.8 Hz, 1H), 4.56 (m, 1H), 5.18 (s, 2H), 6.69 (s, 1H),7.19 (d, J=7.6 Hz, 1H), 7.27-7.39 (m, 4H), 7.44-7.49 (m, 3H), 8.64 (bs,1H).

Example-84 Synthesis of(S)-1-((7-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylbenzyl)oxy)-5-methoxy-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylicacid

Step-1: A mixture of 6-bromo-2,3-dihydrobenzo[b][1,4]dioxine (5 g, 0.023mol),(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol(8.6 g, 0.034 mol), potassium carbonate (9.5 g. 0.069 mol), toluene (50mL), water (50 mL) and EtOH (50 mL) was degassed with nitrogen gas for15 minutes. To this mixture, PdCl₂(dppf)DCM (0.93 g, 1.15 mmol) wasadded and degassed for another 5 minutes with nitrogen. After sealingthe vessel, the mixture was heated at 90° C. for 8 h. After completion,the reaction was diluted with water (300 mL) and extracted with EtOAc(3×300 mL). The organic layer was dried over sodium sulphate andconcentrated. The crude was purified by column chromatography (silicagel, 100-200 mesh) using 0-30% EtOAc in hexanes to obtain(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylphenyl)methanol (Yield:5.8 g, 97%) as yellow sticky liquid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm:2.11 (s, 3H), 4.27 (s, 4H), 4.51 (m, 2H), 5.10 (m, 1H), 6.69-6.74 (m,2H), 6.89 (d, J=7.6 Hz, 1H), 7.04 (d, J=7.6 Hz, 1H), 7.18 (t, J=7.6 Hz,1H), 7.35 (d, J=7.2 Hz, 1H).

Step-2: To a solution of7-hydroxy-5-methoxy-2,3-dihydro-1H-indene-4-carbaldehyde (500 mg, 2.6mmol) and(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylphenyl)methanol (866mg, 3.3 mmol) in dry THF (15 mL) at 0° C., triphenyl phosphine (1.7 g,6.5 mmol) was added and stirred the mixture for 10 minutes at 0° C. Tothis mixture, DEAD (1.355 g, 7.8 mmol) was added and stirred the mixturefor 30 minutes. After completion, the reaction mixture was diluted withwater (20 mL) and extracted with EtOAc (3×25 mL). The organic layer wasdried over sodium sulphate and concentrated. The resulting crude waspurified by flash chromatography (silica gel, 12 g cartridge) using0-30% EtOAc in hexanes as eluent to obtain7-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylbenzyl)oxy)-5-methoxy-2,3-dihydro-1H-indene-4-carbaldehyde(Yield: 350 mg, 27%) as white solid. LCMS (ES) m/z=431.43 [M+H]⁺; ¹H NMR(400 MHz, DMSO-d₆) δ ppm: 1.95-2.01 (m, 2H), 2.23 (s, 3H), 2.71 (m, 2H),3.11 (m, 2H), 3.94 (s, 3H), 4.28 (s, 4H), 5.31 (s, 2H), 6.73-6.79 (m,3H), 6.92 (d, J=8.0 Hz, 1H), 7.18 (d, J=7.6 Hz, 1H), 7.26 (t, J=7.6 Hz,1H), 7.47 (d, J=7.2 Hz, 1H), 10.30 (s, 1H).

Step-3: To a solution of7-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylbenzyl)oxy)-5-methoxy-2,3-dihydro-1H-indene-4-carbaldehyde(100 mg, 0.23 mmol) and (S)-piperidine-2-carboxylic acid (36 mg, 0.27mmol) in DMF (3 mL), acetic acid (3 drops) was added and stirred for 10minutes. To this mixture, sodium cyanoborohydride (43 mg, 0.69 mmol) wasadded and stirred the mixture at 80° C. for 3 h. After completion, thereaction mixture was diluted with ice cold water (10 mL) and extractedwith 10% MeOH in DCM (3× The solid was further dissolved in DCM (30 mL)and dried over sodium sulphate and concentrated. The residue waspurified by flash chromatography (silica gel, 4 g cartridge) using 0-10%MeOH in DCM as eluent. The product was further purified by reverse phaseprep-HPLC using Method-B to obtain(S)-1-((7-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylbenzyl)oxy)-5-methoxy-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylicacid (Yield: 35 mg, 28%) as white solid. LCMS (ES) m/z=544.39 [M+H]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ ppm: 1.38 (m, 1H), 1.48 (m, 3H), 1.76 (m, 2H),1.95-1.98 (m, 2H), 2.22 (s, 3H), 2.42 (m, 1H), 2.73 (m, 2H), 2.82-2.90(m, 2H), 3.00-3.08 (m, 2H), 3.70 (d, J=12.0 Hz, 1H), 3.79 (s, 3H), 3.87(d, J=12.4 Hz, 1H), 4.28 (s, 4H), 5.16 (s, 2H), 6.64 (s, 1H), 6.74-6.78(m, 2H), 6.91 (d, J=8.0 Hz, 1H), 7.16 (d, J=7.2 Hz, 1H), 7.24 (t, J=7.6Hz, 1H), 7.44 (d, J=7.2 Hz, 1H).

The following compounds were prepared following procedures describedabove

Example 85

(2S,4R)-1-((7-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylbenzyl)oxy)-5-methoxy-2,3-dihydro-1H-inden-4-yl)methyl)-4-hydroxypyrrolidine-2-carboxylicacid, LCMS (ES) m/z=546.31 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm:1.95-1.99 (m, 3H), 2.09 (m, 1H), 2.23 (s, 3H), 2.73-2.77 (m, 3H),2.86-2.96 (m, 2H), 3.27 (m, 1H), 3.67 (m, 1H), 3.85 (s, 3H), 4.09 (m,2H), 4.24 (m, 1H), 4.28 (s, 4H), 5.18 (s, 2H), 5.27 (bs, 1H), 6.70 (s,1H), 6.74-6.78 (m, 2H), 6.91 (d, J=8.0 Hz, 1H), 7.16 (d, J=7.2 Hz, 1H),7.25 (t, J=7.6 Hz, 1H), 7.45 (d, J=7.2 Hz, 1H).

Example-86 Synthesis ofN-(2-(((5-((3-cyanobenzyl)oxy)-7-((2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)amino)ethyl)acetamide

Step-1: A mixture of (3-bromo-2-methylphenyl)methanol (2 g, 9.95 mmol),o-tolylboronic acid (4.06 g, 29.84 mmol), sodium carbonate (12.4 g.0.117 mol), toluene (27 mL), water (9 mL) and MeOH (9 mL) was degassedwith nitrogen gas for 15 minutes. To this mixture, Pd(PPh₃)₄ (1.1 g,0.99 mmol) was added and degassed for another 5 minutes with nitrogen.After sealing the vessel, the mixture was heated at 90° C. for 16 h.After completion, the reaction was diluted with water (50 mL) andextracted with EtOAc (3×50 mL). The organic layer was dried over sodiumsulphate and concentrated. The crude was purified by columnchromatography (silica gel, 100-200 mesh) using 0-20% EtOAc in hexane toobtain (2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methanol (Yield: 2.05 g, 97%)as colourless liquid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 1.90 (s, 3H),1.97 (s, 3H), 4.54 (m, 2H), 5.12 (m, 1H), 6.95 (d, J=7.6 Hz, 1H), 7.03(d, J=6.8 Hz, 1H), 7.19-7.28 (m, 4H), 7.39 (d, J=7.2 Hz, 1H).

Step-2: To a solution of (2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methanol(1.7 g, 8.01 mmol) in DCM (5 mL) at 0° C., PBr₃ (2.38 g, 8.8 mmol) wasadded and stirred the mixture at room temperature for 16 h. Aftercompletion, the reaction mixture was concentrated under vacuum and thecrude was purified by flash chromatography (silica gel, 12 g cartridge)using 0-10% EtOAc in hexane as eluent to obtain3-(bromomethyl)-2,2′-dimethyl-1,1′-biphenyl (Yield: 1.7 g, 77%) ascolourless sticky liquid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 1.97 (s, 3H),2.04 (s, 3H), 4.79 (s, 2H), 7.05 (d, J=7.2 Hz, 2H), 7.18-7.33 (m, 4H),7.43 (d, J=8.8 Hz, 1H).

Step-3: To a solution of5,7-dihydroxy-2,3-dihydro-1H-indene-4-carbaldehyde (0.31 g, 1.7 mmol) inacetonitrile (10 mL), potassium carbonate (0.28 g, 2.01 mmol) and3-(bromomethyl)-2,2′-dimethyl-1,1′-biphenyl (0.47 g, 1.7 mmol) wereadded. The reaction mixture was stirred at room temperature for 12 h.After completion, the reaction mixture was diluted with water (20 mL)and extracted with EtOAc (3×20 mL). The combined organic layer was driedover sodium sulfate and concentrated. The resulting crude was purifiedby flash chromatography (silica gel, 4 g cartridge) using 0-30% EtOAc inhexane as eluent to obtain7-((2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-hydroxy-2,3-dihydro-1H-indene-4-carbaldehyde(Yield: 0.61 g, 94%) as light yellow solid. LCMS (ES) m/z=373.16 [M+H]⁺;¹H NMR (400 MHz, DMSO-d₆) δ ppm: 1.97 (s, 3H), 2.02 (m, 2H), 2.04 (s,3H), 2.71 (t, J=7.2 Hz, 2H), 3.14 (t, J=7.2 Hz, 2H), 5.24 (s, 2H), 6.55(s, 1H), 7.05 (d, J=7.2 Hz, 2H), 7.18-7.33 (m, 4H), 7.43 (d, J=8.8 Hz,1H), 10.35 (s, 1H), 11.31 (s, 1H).

Step-4: To a solution of7-((2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-hydroxy-2,3-dihydro-1H-indene-4-carbaldehyde(0.56 g, 1.5 mmol) in DMF (10 mL), potassium carbonate (0.416 g, 3.0mmol) and 3-(chloromethyl)benzonitrile (0.29 g, 1.5 mmol) were added.The reaction mixture was stirred at room temperature for 16 h. Aftercompletion, the reaction mixture was diluted with water (20 mL) andextracted with EtOAc (3×20 mL). The combined organic layer was driedover sodium sulfate and concentrated. The resulting crude was purifiedby flash chromatography (silica gel, 4 g cartridge) using 0-50% EtOAc inhexane as eluent to obtain3-(((7-((2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-4-formyl-2,3-dihydro-1H-inden-5-yl)oxy)methyl)benzonitrile(Yield: 0.705 g, 96%) as light yellow solid. LCMS (ES) m/z=488.41[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 2.00 (m, 2H), 2.02 (s, 3H),2.21 (s, 3H), 2.70 (t, J=7.2 Hz, 2H), 3.13 (m, 2H), 5.12 (s, 2H), 5.20(s, 2H), 6.72 (s, 1H), 7.05-7.07 (m, 2H), 7.23-7.32 (m, 4H), 7.42 (d,J=7.2 Hz, 1H), 7.63 (t, J=7.6 Hz, 1H), 7.85 (m, 2H), 7.96 (s, 1H), 10.37(s, 1H).

Step-5: To a solution of3-(((7-((2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-4-formyl-2,3-dihydro-1H-inden-5-yl)oxy)methyl)benzonitrile(150 mg, 0.30 mmol) in DMF (4 mL) and MeOH (4 mL),N-(2-aminoethyl)acetamide (31 mg, 0.30 mmol) and acetic acid (2 drops)were added and stirred the mixture for 10 minutes. To this mixture,sodium cyanoborohydride (56 mg, 0.90 mmol) was added and the mixture wasstirred at room temperature for 16 h. After completion, the reactionmixture was diluted with water (15 mL) and extracted with 10% MeOH inDCM (3×30 mL). The organic layer was dried over anhydrous sodiumsulphate and concentrated. The resulting crude was purified by flashchromatography (silica gel, 4 g cartridge) using 0-10% MeOH in DCM aseluent. The resulting product was further purified by reverse phase HPLCusing method-A to obtainN-(2-(((5-((3-cyanobenzyl)oxy)-7-((2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)amino)ethyl)acetamide(Yield: 100 mg, 21%) as white solid. LCMS (ES) m/z=574.52 [M+H]⁺; ¹H NMR(400 MHz, DMSO-d₆) δ ppm: 1.74 (s, 3H), 1.96-2.00 (m, 8H), 2.53 (m, 2H),2.73 (t, J=7.2 Hz, 2H), 2.88 (t, J=7.2 Hz, 2H), 3.13 (m, 2H), 3.64 (s,2H), 5.12 (s, 2H), 5.20 (s, 2H), 6.71 (s, 1H), 7.05-7.07 (m, 2H),7.23-7.32 (m, 4H), 7.42 (d, J=7.2 Hz, 1H), 7.61 (t, J=7.6 Hz, 1H), 7.75(m, 1H), 7.80-7.82 (m, 2H), 7.94 (s, 1H),

The following compounds were prepared following procedures describedabove

Example 87

N-(2-(((5-((3-cyanobenzyl)oxy)-7-((4′-fluoro-2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)amino)ethyl)acetamide,LCMS (ES) m/z=578.44 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 1.79 (s,3H), 1.96-2.01 (m, 2H), 2.18 (s, 3H), 2.77 (t, J=7.2 Hz, 2H), 2.90-2.97(m, 4H), 3.27 (m, 2H), 4.00 (s, 2H), 5.17 (s, 2H), 5.28 (s, 2H), 6.79(s, 1H), 7.19 (d, J=7.2 Hz, 1H), 7.23-7.37 (m, 5H), 7.41 (d, J 7.2 Hz,1H), 7.62 (t, J=7.6 Hz, 1H), 7.81-7.87 (m, 2H), 8.00 (bs, 1H), 8.07 (bs,1H),

Example-88 Synthesis of(S)-1-((5-((3-carbamoylbenzyl)oxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylicacid

To a solution of(S)-1-((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylicacid (90 mg, 0.15 mmol) in MeOH (5 mL), water (5 mL), 1,4-dioxane (3mL), and sodium hydroxide (10 mg) were added and stirred the mixture at90° C. for 3 h. After completion, the reaction mixture was diluted withwater (10 mL) and extracted with 10% MeOH in DCM (3×20 mL). The organiclayer was concentrated and the crude was purified by flashchromatography (silica gel, 4 g cartridge) using 0-15% MeOH in DCM toobtain(S)-1-((5-((3-carbamoylbenzyl)oxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylicacid (Yield: 40 mg, 44%) as white solid. LCMS (ES) m/z=605.37 [M+H]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ ppm: 1.33-1.48 (m, 4H), 1.79 (m, 2H), 1.95-1.99(m, 2H), 2.21 (s, 3H), 2.74 (m, 2H), 2.83 (m, 1H), 2.96-3.02 (m, 3H),3.17 (m, 1H), 3.82 (d, J=12.0 Hz, 1H), 4.04 (d, J=12.8 Hz, 1H), 5.15 (s,2H), 5.23 (s, 2H), 6.79 (bs, 1H), 7.19 (m, 1H), 7.25-7.33 (m, 4H), 7.39(m, 1H), 7.44-7.48 (m, 4H), 7.65 (d, J=8.0 Hz, 1H), 7.83 (d, J=7.6 Hz,1H), 8.12 (s, 1H), 8.31 (bs, 1H).

Example-89 Synthesis of3-(((4-(aminomethyl)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)benzonitrile

Step-1: To a solution of3-(((4-formyl-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)benzonitrile(60 mg, 0.126 mmol) in MeOH (2 mL), THF (2 mL) at 0° C., sodiumborohydride (12 mg, 0.40 mmol) was added slowly and allowed the mixtureto stir at RT for 3 h. After completion, the reaction was quenched withwater (10 mL) and extracted with DCM (2×100 mL). The organic layer wasdried over anhydrous sodium sulfate and concentrated. The resultingcrude was purified by flash chromatography using 30% EtOAc in hexanes aseluent to obtain3-(((4-(hydroxymethyl)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl) oxy) methyl) benzonitrile (Yield: 50mg, 83%) as white solid. LCMS (ES) m/z=476 [M−H]⁺; ¹H NMR (400 MHz,DMSO-d₆) δ ppm: 1.94-2.02 (m, 2H), 2.19 (s, 3H), 2.74 (m, 2H), 2.91 (m,2H), 4.45 (m, 2H), 4.54 (m, 1H), 5.13 (s, 2H), 5.20 (s, 2H), 6.69 (s,1H), 7.32 (d, J=7.28 Hz, 1H) 7.35-7.47 (m, 4H), 7.60 (m, 1H), 7.81 (m,2H), 7.95 (s, 1H).

Step-2: To a solution of3-(((4-(hydroxymethyl)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl) oxy) methyl) benzonitrile (250 mg,0.526 mmol) and pthalimide (229 mg, 1.31 mmol) in dry THF (5 mL),triphenyl phosphine (345 mg, 1.31 mmol) was added and cooled the mixtureto 0° C. To this mixture, DIAD (266 mg, 1.31 mmol) was added and allowedthe mixture to stir at room temperature for 6 h. After completion, thereaction mixture was diluted with water (20 mL) and extracted with EtOAc(3×40 mL). The combined organic layer was dried over sodium sulphate andconcentrated. The crude was purified by flash chromatography using 20%EtOAc in hexane as eluent to obtain3-(((4-((1,3-dioxoisoindolin-2-yl)methyl)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)benzonitrile(Yield: 300 mg, 94%) as white solid. LCMS (ES) m/z=605.31 [M+H]⁺

Step-3: To a solution of3-(((4-((1,3-dioxoisoindolin-2-yl)methyl)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)benzonitrile(300 mg, 0.495 mmol) in EtOH (15 mL), at room temperature, hydrazinehydrate solution (2 mL) was added slowly and allowed to stir the mixtureat RT for 3 h. After completion, the reaction was quenched with water(10 mL) and extracted with DCM (2×100 mL). The organic layer was driedover anhydrous sodium sulfate and concentrated. The resulting crude waspurified by flash chromatography using 30% EtOAc in hexanes as eluent toobtain3-(((4-(aminomethyl)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)benzonitrile(Yield: 35 mg, 15%) as white solid. LCMS (ES) m/z=475.6 [M+H]⁺; ¹H NMR(400 MHz, DMSO-d₆) δ ppm: 1.98 (m, 2H), 2.19 (s, 3H), 2.74 (m, 2H), 2.89(m, 2H), 3.62 (s, 2H), 5.12 (s, 2H), 5.21 (s, 2H), 6.69 (s, 1H), 7.17(d, J=7.24 Hz, 1H), 7.25 (m, 1H), 7.32 (d, J=7.04 Hz, 1H), 7.37-7.47 (m,4H), 7.59 (m, 1H), 7.78-7.86 (m, 2H), 7.91 (m, 1H).

Example-90 Synthesis ofN-((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)acetamide

Step-1: A solution of3-(((4-(aminomethyl)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)benzonitrile(40 mg, 0.084 mmol), triethylamine (12.7 mg, 0.21 mmol) in DCM (5 mL)was cooled to 0° C. To this mixture, acetyl chloride (16 mg, 0.021 mmol)was added and the reaction mixture was stirred at room temperature for 6h. After completion of the reaction, the reaction mixture was dilutedwith ice cold water (10 mL) and the aqueous mixture was extracted withEtOAc (3×100 mL). The combined organic layer was dried over sodiumsulfate and concentrated. The resulting crude was purified by flashchromatography (silica gel, 4 g cartridge) using 0-30% EtOAc in hexanesas eluent to obtain N-((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl) acetamide (Yield: 32 mg, 73%) as white solid. LCMS (ES)m/z=517.34 [M−H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 1.79 (s, 3H), 1.98(m, 2H), 2.19 (s, 3H), 2.74 (m, 2H), 2.87 (m, 2H), 4.21 (m, 2H), 5.12(s, 2H), 5.21 (s, 2H), 6.72 (s, 1H), 7.19 (d, J=7.08 Hz, 1H), 7.25 (m,1H), 7.32 (d, J=7.04 Hz, 2H), 7.40-7.47 (m, 4H), 7.59 (m, 1H), 7.78-7.82(m, 3H), 7.91 (s, 1H).

Example-91 Synthesis of6-acetamido-N-((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)hexanamide

Step-1: A solution of3-(((4-(aminomethyl)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)benzonitrile(150 mg, 0.31 mmol), 6-acetamidohexanoic acid (82 mg, 0.47 mmol), HOBt(64 mg, 0.47 mmol), EDC.HCl (90 mg, 0.47 mmol) and DIPEA (244 mg, 1.89mmol) in DMF (10 mL) was stirred for 12 h at room temperature. Aftercompletion of the reaction, the reaction mixture was diluted with icecold water (20 mL) and extracted with 10% MeOH in DCM (2×50 mL). Thecombined organic layer was washed with brine solution (20 mL), driedover sodium sulfate and concentrated. The resulting crude was purifiedby flash chromatography (silica gel, 4 g cartridge) using 0-10% MeOH inDCM as eluent to obtain6-acetamido-N-((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)hexanamide(Yield: 80 mg, 40%) as white solid. LCMS (ES) m/z=630.68 [M−H]⁺; ¹H NMR(400 MHz, DMSO-d₆) δ ppm: 1.16-1.21 (m, 2H), 1.29-1.36 (m, 2H),1.41-1.49 (m, 2H), 1.75 (s, 3H), 1.93-2.06 (m, 4H), 2.19 (s, 3H),2.66-2.74 (m, 2H), 2.87 (m, 2H), 2.96 (m, 2H), 4.21 (m, 2H), 5.13 (s,2H), 5.21 (s, 2H), 6.72 (s, 1H), 7.19 (d, J=7.36 Hz, 1H), 7.25 (m, 1H),7.32 (d, J=7.04 Hz, 1H), 7.37-7.47 (m, 4H), 7.59 (t, J=7.76 Hz, 1H),7.78-7.82 (m, 4H), 7.93 (s, 1H).

Example-92 Synthesis of3-(((4-((dimethylamino)methyl)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)benzonitrile

Step-1: A solution of3-(((4-formyl-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)benzonitrile(120 mg, 0.25 mmol), dimethylamine solution in methanol (4 mL), andacetic acid (1 drop) in DMF (4 mL) was stirred at room temperature for 2h. To this mixture, sodium cyanoborohydride (47 mg, 0.76 mmol) was addedand stirred for 12 h. After completion, the reaction mixture was pouredon ice cold water (10 mL) and collected the white solid by filtration. Asolution of white solid in DCM (20 mL) was dried over sodium sulfate andconcentrated. The resulting crude was purified by flash chromatography(silica gel, 4 g cartridge) using 0-10% MeOH in DCM as eluent to obtain3-(((4-((dimethylamino)methyl)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)benzonitrile (Yield: 12mg, 9.6%) as white solid. LCMS (ES) m/z=503.5 [M−H]⁺; ¹H NMR (400 MHz,DMSO-d₆) δ ppm: 2.01 (m, 2H), 2.20 (s, 3H), 2.62-2.79 (m, 8H), 2.97 (m,2H), 4.20 (m, 2H), 5.19 (s, 2H), 5.30 (s, 2H), 6.84 (s, 1H), 7.19 (d,J=7.08 Hz, 1H), 7.25-7.32 (m, 3H), 7.38-7.48 (m, 4H), 7.62 (t, J=7.04Hz, 1H), 7.82-7.88 (m, 2H), 8.03 (s, 1H).

Example-93 Synthesis of5-(((4-(((2-acetamidoethyl)amino)methyl)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)nicotinicacid

To a solution ofN-(2-(((5-((5-cyanopyridin-3-yl)methoxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)amino)ethyl)acetamide(0.12 g, 0.21 mmol) in ethanol (8 mL) and water (8 mL), potassiumhydroxide (60 mg, 1.07 mmol) was added and refluxed for 20 h. Aftercompletion, the reaction mixture was diluted with water (20 mL) andwashed with EtOAc (30 mL). The aqueous layer was acidified to pH 4 using6N HCl solution and then the mixture was extracted with 10% MeOH in DCM(2×100 mL). The combined organic layer was dried over sodium sulfate andconcentrated. The resulting crude was purified by flash chromatography(silica gel, 4 g cartridge) using 0-10% MeOH in DCM as eluent. Thecompound was further purified by reverse phase HPLC using method-B toobtain5-(((4-(((2-acetamidoethyl)amino)methyl)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)nicotinicacid (Yield: 20 mg, 16%) as white solid. LCMS (ES) m/z=580.58 [M+H]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ ppm: 1.76 (s, 3H), 2.00 (m, 2H), 2.20 (s, 3H),2.74-2.83 (m, 4H), 2.94 (m, 2H), 3.25 (m, 2H), 3.87 (s, 2H), 5.18 (s,2H), 5.27 (s, 2H), 6.85 (s, 1H), 7.18 (d, J=7.6 Hz, 1H), 7.24-7.32 (m,3H), 7.39 (m, 1H), 7.43-7.48 (m, 3H), 8.32 (s, 1H), 8.40 (br, 1H), 8.74(s, 1H), 8.96 (s, 1H).

Example-94 Synthesis of5-(((4-(((2-acetamidoethyl)amino)methyl)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)nicotinamide

Step-1: To a solution ofN-(2-(((5-((5-cyanopyridin-3-yl)methoxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)amino)ethyl)acetamide(1, 0.15 g, 0.25 mmol) in Ethanol (8 mL) and water (8 mL), potassiumhydroxide (60 mg, 1.07 mmol) was added and refluxed for 6 h. Aftercompletion, the reaction mixture was diluted with water (20 mL) andwashed with EtOAc (30 mL). The aqueous layer was acidified to pH 4 using6N HCl solution and the reaction mixture was extracted with 10% MeOH inDCM (2×100 mL). The combined organic layer was dried over sodium sulfateand concentrated. The resulting crude was purified by flashchromatography (silica gel, 4 g cartridge) using 0-10% MeOH in DCM aseluent. The compound was further purified by reverse phase HPLC usingmethod-B to obtain5-(((4-(((2-acetamidoethyl)amino)methyl)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)nicotinamide(Yield: 30 mg, 20%) as white solid. LCMS (ES) m/z=579.6 [M+H]⁺; ¹H NMR(400 MHz, DMSO-d₆) δ ppm: 1.74 (s, 3H), 1.84 (m, 2H), 1.97 (m, 2H), 2.20(s, 3H), 2.74 (m, 2H), 2.87 (m, 2H), 3.07 (m, 2H), 3.61 (s, 2H), 5.13(s, 2H), 5.25 (s, 2H), 6.77 (s, 1H), 7.18 (d, J=7.6 Hz, 1H), 7.31-7.33(m, 2H), 7.39 (m, 1H), 7.43-7.48 (m, 3H), 7.64 (m, 1H), 7.73 (m, 1H),8.21 (bs, 1H), 8.32 (s, 1H), 8.32 (s, 1H), 8.81 (s, 1H), 8.99 (s, 1H).

Example-95 Synthesis of3-(((4-(((2-acetamidoethyl)amino)methyl)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)benzamide

Step-1: To a solution of3-(((4-formyl-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)benzonitrile(0.30 g, 0.63 mmol) in ethanol (10 mL) and water (10 mL), potassiumhydroxide (0.15 g, 2.67 mmol) was added and refluxed for 12 h. Aftercompletion, the reaction mixture was diluted with water (20 mL) andextracted with EtOAc (30 mL). The aqueous layer was acidified to pH 4using 6N HCl solution and the reaction mixture was extracted with 10%MeOH in DCM (2×100 mL). The combined organic layer was dried over sodiumsulfate and concentrated. The resulting crude provided a mixture of3-(((4-formyl-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)benzamide (240 mg; crude)as yellow viscous liquid which was used in next step without furtherpurification.

Step-2: A solution of3-(((4-formyl-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)benzamide(240 mg, 0.487 mmol), N-(2-aminoethyl)acetamide (50 mg, 0.487 mmol) andacetic acid (1 drop) in DMF (4 mL) and MeOH (4 mL) was stirred at roomtemperature for 2 h. To this mixture, sodium cyanoborohydride (92 mg,1.46 mmol) was added and the reaction mixture was stirred for 16 h.After completion of the reaction, the reaction mixture was diluted withice cold water (10 mL) and the aqueous mixture was extracted with 10%MeOH in DCM (3×100 mL). The combined organic layer was dried over sodiumsulfate and concentrated. The resulting crude was purified by flashchromatography (silica gel, 4 g cartridge) using 0-10% MeOH in DCM aseluent to obtain 3-(((4-(((2-acetamidoethyl)amino)methyl)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)benzamide(32 mg) as white solid. LCMS (ES) m/z=578.62 [M+H]⁺; ¹H NMR (400 MHz,DMSO-d₆) δ ppm: 1.73 (s, 3H), 1.99 (m, 2H), 2.20 (s, 3H), 2.53 (m, 2H),2.74 (m, 2H), 2.87 (m, 2H), 3.07 (m, 2H), 3.62 (s, 2H), 5.12 (s, 2H),5.18 (s, 2H), 6.74 (s, 1H), 7.18 (d, J=7.26 Hz, 1H), 7.26 (m, 1H), 7.31(d, J=8.16 Hz, 2H), 7.36-7.48 (m, 6H), 7.61 (d, J=7.6 Hz, 1H), 7.74 (m,1H), 7.82 (d, J=7.76 Hz, 1H), 8.01 (m, 2H).

Example-96 Synthesis of(S)-1-((3-methoxy-1-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)methyl)piperidine-2-carboxylicacid

Step-1: To a solution of cyclopentanone (40 g, 476.19 mmol) andmalononitrile (30 mL, 476.19 mmol) in MeOH (100 mL) and DMF (30 mL), CS₂(100 mL, 1664.2 mmol) was added and stirred for 5 minutes. To thismixture, triethylamine (35 mL, 237.7 mmol) was slowly added drop wiseand stirred the mixture at room temperature for 48 h. After completion,the reaction mixture was filtered and washed with cold MeOH (30 mL) anddried under vacuum to obtain3-hydroxy-1-mercapto-6,7-dihydro-5H-cyclopenta[c]pyridine-4-carbonitrile(Yield: 13.0 g, crude) as red solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm:1.86-1.96 (m, 2H), 2.74 (t, J=8.0 Hz, 2H), 2.93 (t, J=8.0 Hz, 2H), 8.75(s, 1H), 9.03 (s, 1H).

Step-2: A solution of3-hydroxy-1-mercapto-6,7-dihydro-5H-cyclopenta[c]pyridine-4-carbonitrile(13 g, 67.56 mmol) in 1N NaOH (250 mL) was stirred at 150° C. for 8 h.After completion, the reaction mixture was acidified with aqueous 6N HClsolution and filtered the solid. The solid was washed with cold water(20 mL) and dried under vacuum to obtain1-mercapto-6,7-dihydro-5H-cyclopenta[c]pyridin-3-ol (Yield: 6.2 g,crude) as red solid. LCMS (ES) m/z=168.32 [M+H]⁺; ¹H NMR (400 MHz,DMSO-d₆) δ ppm: 1.90 (t, J=8.0 Hz, 2H), 2.60 (t, J=8.0 Hz, 2H), 2.78 (t,J=8.0 Hz, 2H), 5.94 (s, 1H), 11.50-12.76 (bs, 2H).

Step-3: To a solution of1-mercapto-6,7-dihydro-5H-cyclopenta[c]pyridin-3-ol (4.0 g, 23.95 mmol)in EtOH (100 mL), potassium carbonate (5.0 g, 36.17 mmol) and MeI (3.39g, 2.39 mmol) were added and stirred the mixture at room temperature for6 h. After completion, the reaction was quenched with water (100 mL) andextracted with DCM (2×100 mL). The organic layer was dried overanhydrous sodium sulfate and concentrated. The resulting crude waspurified by flash chromatography (silica gel, 12 g cartridge) using0-30% EtOAc in hexanes as eluent to obtain1-(methylthio)-6,7-dihydro-5H-cyclopenta[c]pyridin-3-ol (Yield: 1.9 g,44%) as red solid. LCMS (ES) m/z=182.31 [M+H]⁺; ¹H NMR (400 MHz,DMSO-d₆) δ ppm: 1.96-2.01 (m, 2H), 2.49 (s, 3H), 2.57 (t, J=8.0 Hz, 2H),2.75 (t, J=8.0 Hz, 2H), 6.18 (s, 1H), 10.44 (s, 1H).

Step-4: To a solution of1-(methylthio)-6,7-dihydro-5H-cyclopenta[c]pyridin-3-ol (3.0 g, 16.55mmol) in benzene (50 mL), Ag₂O (2.18 g, 9.40 mmol) and MeI (2.58 g,18.23 mmol) were added and stirred the mixture at 80° C. for 16 h. Aftercompletion, the reaction was quenched with water (100 mL) and extractedwith EtOAc (2×100 mL). The organic layer was dried over anhydrous sodiumsulfate and concentrated. The resulting crude was purified by flashchromatography (silica gel, 12 g cartridge) using 10% EtOAc in hexanesas eluent to obtain3-methoxy-1-(methylthio)-6,7-dihydro-5H-cyclopenta[c]pyridine (Yield:2.3 g, 71%) as white solid. LCMS (ES) m/z=196.35 [M+H]⁺; ¹H NMR (400MHz, DMSO-d₆) δ ppm: 2.06-1.99 (m, 2H), 2.49 (s, 3H), 2.60 (t, J=7.2 Hz,2H), 2.80 (t, J=8.0 Hz, 2H), 3.85 (s, 3H), 6.39 (s, 1H).

Step-5: To a solution of3-methoxy-1-(methylthio)-6,7-dihydro-5H-cyclopenta[c]pyridine (2.3 g,11.73 mmol) in DCM (30 mL), Br₂ (2.0 g, 11.73 mmol) was added slowly andstirred at room temperature for 4 h. After completion, the reaction wasconcentrated under vacuum to obtain4-bromo-3-methoxy-1-(methylthio)-6,7-dihydro-5H-cyclopenta[c]pyridine(Yield: 2.0 g, 62%) as off-white solid. LCMS (ES) m/z=274.31 [M+H]⁺ &276.32 [M+2H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 2.06-2.12 (m, 2H), 2.54(s, 3H), 2.73 (t, J=8 Hz, 2H), 2.85 (t, J=8.0 Hz, 2H), 3.94 (s, 3H).

Step-6: To a solution of4-bromo-3-methoxy-1-(methylthio)-6,7-dihydro-5H-cyclopenta[c]pyridine(2.0 g, 10.24 mmol) in DCM (50 mL) at 0° C., mCPBA (4.0 g, 25.60 mmol)was added and stirred the mixture at room temperature for 12 h. Aftercompletion, the reaction was quenched with aqueous saturated NaHCO₃solution (100 mL) and extracted with DCM (2×70 mL). The organic layerwas dried over anhydrous sodium sulfate and concentrated under vacuum toobtain4-bromo-3-methoxy-1-(methylsulfonyl)-6,7-dihydro-5H-cyclopenta[c]pyridine(Yield: 1.9 g, 80%) as white solid. LCMS (ES) m/z=306.25 [M+H]⁺ & 308.21[M+2H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 2.10-2.13 (m, 2H), 2.92 (t,J=8 Hz, 2H), 3.23 (t, J=8.0 Hz, 2H), 3.30 (s, 3H), 3.97 (s, 3H).

Step-7: To a solution of (2-methyl-[1,1′-biphenyl]-3-yl)methanol (0.92g, 4.64 mmol) in DMF (10 mL) at 0° C., NaH (0.25 g, 6.37 mmol) was addedand stirred at 0° C. for 30 min. To this mixture,4-bromo-3-methoxy-1-(methylsulfonyl)-6,7-dihydro-5H-cyclopenta[c]pyridine(1.3 g, 4.24 mmol) was added and stirred the mixture at room temperaturefor 6 h. After completion, the reaction mixture was quenched withaqueous saturated NaHCO₃ solution (100 mL) and extracted with EtOAc(2×80 mL). The organic layer was dried over anhydrous sodium sulfate andconcentrated. The resulting crude was purified by flash chromatography(silica gel, 4 g cartridge) using DCM as eluent to obtain4-bromo-3-methoxy-1-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-6,7-dihydro-5H-cyclopenta[c]pyridine(Yield: 700 mg, 39%) as white solid. LCMS (ES) m/z=424.38[M+H]⁺ and426.39 [M+2H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 2.06 (t, J=8.0 Hz, 2H),2.16 (s, 3H), 2.83 (m, 4H), 3.91 (s, 3H), 5.46 (s, 2H), 7.16-7.18 (m,1H), 7.24-7.27 (m, 1H), 7.29-7.31 (m, 2H), 7.35-7.39 (m, 1H), 7.43-7.46(m, 3H).

Step-8: To a solution of4-bromo-3-methoxy-1-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-6,7-dihydro-5H-cyclopenta[c]pyridine(0.7 g, 1.64 mmol) in DMF (20 mL), tributyl(vinyl)tin (1.3 g, 4.10 mmol)was added and degassed with nitrogen gas for 5 min. To this mixture,Pd(PPh₃)₄ (0.2 g, 0.16 mmol) was added and degassed again with nitrogengas for 5 min. The mixture was stirred at 90° C. for 16 h. Aftercompletion, the reaction was quenched with water (30 mL) and extractedwith EtOAc (2×80 mL). The organic layer was dried over anhydrous sodiumsulfate and concentrated. The resulting crude was purified by flashchromatography (silica gel, 4 g Cartridge) using hexane as eluent toobtain3-methoxy-1-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-4-vinyl-6,7-dihydro-5H-cyclopenta[c]pyridine(Yield: 550 mg, 89%) as white solid. LCMS (ES) m/z=372.48 [M+H]⁺; ¹H NMR(400 MHz, DMSO-d₆) δ ppm: 2.03-2.08 (m, 2H), 2.22 (s, 3H), 2.71-2.94 (m,4H), 3.91 (s, 3H), 5.27 (d, J=11.6 Hz, 1H), 5.48 (s, 2H), 5.67 (d,J=18.8 Hz, 1H), 7.17 (m, 1H), 7.23-7.27 (m, 1H), 7.29-7.31 (m, 2H),7.35-7.38 (m, 1H), 7.43-7.47 (m, 3H).

Step-9: A solution of3-methoxy-1-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-4-vinyl-6,7-dihydro-5H-cyclopenta[c]pyridine(0.55 g, 1.48 mmol) in THF (3 mL) and water (3 mL) was cooled to 0° C.,Osmium tetroxide (0.41 g, 1.62 mmol) was added and stirred at 0° C. for15 min. To this mixture, NaIO₄ (1.1 g, 5.18 mmol) was added and stirredthe mixture at room temperature for 16 h. After completion, the reactionwas quenched with water (10 mL) and extracted with Et₂O (2×20 mL). Theorganic layer was dried over anhydrous sodium sulfate and concentrated.The resulting crude was purified by flash chromatography (silica gel, 4g cartridge) using 0-20% EtOAc in hexanes as eluent to obtain3-methoxy-1-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-6,7-dihydro-5H-cyclopenta[c]pyridine-4-carbaldehyde(Yield: 220 mg, 40%) as white solid. LCMS (ES) m/z=374.47 [M+H]⁺.

Step-10: A solution of3-methoxy-1-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-6,7-dihydro-5H-cyclopenta[c]pyridine-4-carbaldehyde(90 mg, 0.241 mmol), (S)-piperidine-2-carboxylic acid (37 mg, 0.289mmol), sodium cyanoborohydride (44 mg, 0.71 mmol) and acetic acid (2drops) in DMF (5 mL) was stirred at 80° C. for 6 h. After completion,the reaction mixture was poured on ice cold water (10 mL) and extractedwith 10% MeOH in DCM (2×30 mL). The organic layer was dried overanhydrous sodium sulfate and concentrated. The resulting crude waspurified by flash chromatography (silica gel, 4 g cartridge) using 0-10%MeOH in DCM as eluent to obtain(S)-1-((3-methoxy-1-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)methyl)piperidine-2-carboxylicacid (Yield: 35 mg, 30%) as white solid. LCMS (ES) m/z=487.46 [M+H]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ ppm: 1.39-1.48 (m, 4H), 1.70-1.78 (m, 2H), 2.02(t, J=8 Hz, 2H), 2.22 (s, 3H), 2.36-2.43 (m, 1H), 2.71 (t, J=8 Hz, 2H),2.85-3.06 (m, 3H), 3.68-3.77 (m, 1H), 3.78-3.80 (m, 1H), 3.85 (s, 3H),5.45 (s, 2H), 7.17 (d, J=8 Hz, 1H), 7.25 (t, J=8 Hz, 1H), 7.30 (d, J=8Hz, 2H), 7.37 (t, J=8.0 Hz, 1H), 7.44 (t, J=8.0 Hz, 3H).

The following compound were prepared following procedures describedabove

Example 97

N-(2-(((3-methoxy-1-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)methyl)amino)ethyl)acetamide,LCMS (ES) m/z=460.40 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 1.76 (s,3H), 2.02 (t, J=7.2 Hz, 2H), 2.22 (s, 3H), 2.47 (t, J=7.6 Hz, 2H), 2.72(t, J=7.2 Hz, 2H), 2.86 (t, J=7.2 Hz, 2H), 3.09 (t, J=6.0 Hz, 2H), 3.54(s, 2H), 3.85 (s, 3H), 5.44 (s, 2H), 7.16 (t, J=7.6 Hz, 1H), 7.25 (t,J=7.6 Hz, 1H), 7.30 (d, J=7.6 Hz, 2H), 7.37 (t, J=6.8 Hz, 1H), 7.45 (t,J=6.8 Hz, 3H), 7.73 (m, 1H).

Example-98 Synthesis of(S)-4-((5-methoxy-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)morpholine-3-carboxylicacid

Step-1: A solution of5-methoxy-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-indene-4-carbaldehyde(150 mg, 0.403 mmol), (S)-morpholine-3-carboxylic acid (158 mg, 1.209mmol),) in DMF (3 mL) and MeOH (3 mL), AcOH (2 drops) was added andstirred for 2 h at room temperature. To this mixture, sodiumcyanoborohydride (74 mg, 1.20 mmol) was added and continued stirring for16 h. After completion, the reaction mixture was poured on to ice-coldwater (10 mL) and extracted with 10% MeOH in DCM (3×20 mL). The organiclayer was dried over sodium sulfate and concentrated. The resultingcrude was purified by flash chromatography (silica gel, 4 g cartridge)using 0-10% MeOH in DCM as eluent to obtain(S)-4-((5-methoxy-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)morpholine-3-carboxylicacid (Yield: 12 mg, 6%) as white solid. LCMS (ES) m/z=486.37 [M+H]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ ppm: 1.95-1.98 (m, 2H), 2.22 (m, 3H), 2.26-2.32(m, 2H), 2.74 (m, 2H), 2.84 (m, 1H), 2.93-2.99 (m, 2H), 3.11 (m, 1H),3.46 (m, 1H), 3.55 (m, 1H), 3.68 (m, 2H), 3.75 (s, 4H), 5.17 (s, 2H),6.62 (s, 1H), 7.19 (d, J=7.6 Hz, 1H), 7.25-7.33 (m, 3H), 7.37 (m, 1H),7.44-7.49 (m, 3H).

Example-995-((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylicacid

The compound was synthesized according to the procedure out lined in theexample 15, LCMS (ES) m/z=625.35 [M+H]⁺,

General Procedure for Biological Evaluation PD-Li Enzyme Assay:Homogenous Time-Resolved Fluorescence (HTRF) Binding Assay

All binding studies were performed using PD-1/PD-L1 Binding Assay Kitfrom CisBio (Catalog #63ADK000CPAPEG), according to the manufacturer'sprotocol. The interaction between Tag1-PD-1 and Tag2-PD-1 was detectedby anti-Tag1-Eu³⁺ (HTRF donor) and anti-Tag2-XL665 (HTRF acceptor). Whenthe donor and acceptor antibodies were brought to close proximity due toPD-1 and PD-L1 binding, excitation of the donor antibody triggeredfluorescent resonance energy transfer (FRET) towards the acceptorantibody, which in turn emitted specifically at 665 nm. This specificsignal is positively proportional to PD-1/PD-L1 interaction. Thecompounds blocking PD-1/PD-L1 interaction will cause a reduction in HTRFsignal. The necessary reagents were mixed in the following order: 2 μlcompounds (or diluents buffer), 4 μl PD-L1 protein, 4 μl PD-1 protein.After an incubation of 15 minutes, 5 μl of anti-Tag1-Eu³⁺ and 5 μl ofanti-Tag2-XL665 were added. The plate was sealed and incubated at roomtemperature for 1 h. The fluorescence emission was read at two differentwavelengths (665 nm and 620 nm) on a BMG PheraStar® multi-plate reader.Results were calculated from the 665 nm and 620 nm fluorescence signaland expressed in HTRF ratio=(665 nm/620 nm)×10⁴.

Evaluation of Biological Activity:

Table 5, below, shows the biological activity of compounds of thepresent invention in PD1/PD-Li inhibition assay. Compounds havingIC50<100 nM are designated as “A”; 100-500 nM are designated as “B”;and >500 nM are designated as “C” respectively.

TABLE 5 Biochemical PD1/PD-L1 inhibition data Compound PD1/PD-L1Activity 1 B 2 B 3 C 4 B 5 B 6 C 7 C 8 A 9 A 10 A 11 A 12 A 13 A 14 C 15A 16 C 17 C 18 B 19 B 20 B 21 C 22 B 23 C 24 C 25 A 26 B 27 B 28 C 29 B30 B 31 B 32 B 33 C 34 A 35 A 36 A 37 A 38 A 39 B 40 A 41 A 42 A 43 A 44A 45 B 46 A 47 A 48 A 49 A 50 A 51 A 52 A 53 A 54 B 55 A 56 A 57 A 58 A59 A 60 A 61 A 62 A 63 B 64 B 65 A 66 B 67 A 68 A 69 A 70 A 71 A 72 A 73B 74 A 75 C 76 C 77 A 78 A 79 A 80 C 81 A 82 B 83 B 84 A 85 B 86 B 87 B88 B 89 A 90 C 91 C 92 A 93 A 94 A 95 A 96 ND 97 A 98 A 99 ND ND—notdetermined

The above-mentioned compounds have potential to be developed as drugs toalleviate the PD1/PD-L1 activity and thus treating cancer, and otherdiseases or conditions associated with activation of PD1/PD-L1.

1. A compound of Formula I

their polymorphs, stereoisomers, tautomer's, prodrugs, solvates, and pharmaceutically acceptable salts thereof, wherein X₁ is selected from —CH₂O—, —OCH₂—, —C(O)NH— or —NHC(O)—; R₄ is selected from hydrogen, C₁₋₆ alkyl, —C(O)OR_(a1), C(O)NR_(b1)R_(c1), C₅₋₆ aryl, or C₁₋₆ heteroaryl, wherein C₁₋₆ alkyl is optionally substituted with one or more of the groups selected from the group consisting of hydrogen, hydroxyl, amino, —C(O)OR_(a1), C(O)NR_(b1)R_(c1), C₅₋₆ aryl, and C₁₋₆ heteroaryl; R_(a1), R_(b1), and R_(c1) are independently selected from hydrogen or C₁₋₆ alkyl; X is selected from CR₃ or N; R₁, R₂, R₃, R₆, and R₇ are independently selected from hydrogen, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-14 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a), SR^(a), NHOR^(a), C(O)R^(a), C(O)NR^(a)R^(a), C(O)OR^(a), OC(O)R^(a), OC(O)NR^(a)R^(a), NHR^(a), NR^(a)R^(a), NR^(a)C(O)R^(a), NR^(a)C(O)OR^(a), NR^(a)C(O)NR^(a)R^(a), C(═NR^(a))R^(a), C(═NR^(a))NR^(a)R^(a), NR^(a)C(═NR^(a))NR^(a)R^(a), NR^(a)S(O)R^(a), NR^(a)S(O)₂R^(a), NR^(a)S(O)₂NR^(a)R^(a), S(O)R^(a), S(O)NR^(a)R^(a), S(O)₂R^(a), or S(O)₂NR^(a)R^(a), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-14 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, are independently optionally substituted with 1, 2, 3, or 4 R^(b) substituents; R^(a) is selected from hydrogen, cyano, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, or (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are independently optionally substituted with 1, 2, 3, 4, or 5 R^(d) substituents; R^(b) is selected from halo, hydroxy, cyano, amino, nitro, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, NHOR^(c), OR^(c), SR^(c), C(O)R^(c), C(O)NR^(c)R^(c), C(O)OR^(c), OC(O)R^(c), OC(O)NR^(c)R^(c), C(═NR^(c))NR^(c)R^(c), NR^(c)C(═NR^(c))NR^(c)R^(c), NHR^(c), NR^(c)R^(c), NR^(c)C(O)R^(c), NR^(c)C(O)OR^(c), NR^(c)C(O)NR^(c)R^(c), NR^(c)S(O)R^(c), NR^(c)S(O)₂R^(c), NR^(c)S(O)₂NR^(c)R^(c), S(O)R^(c), S(O)NR^(c)R^(c), S(O)₂R^(c) or S(O)₂NR^(c)R^(c); wherein the C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are optionally substituted with 1, 2, or 3 R^(d) substituents; R^(c) is selected from hydrogen, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, or (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are optionally substituted with 1, 2, 3, 4, or 5 R^(f) substituent; R^(d) is selected from cyano, amino, C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, NHOR^(e), OR^(e), SR^(e), C(O)R^(e), C(O)NR^(e)R^(e), C(O)OR^(e), OC(O)R^(e), OC(O)NR^(e)R^(e), NHR^(e), NR^(e)R^(e), NR^(e)C(O)R^(e), NR^(e)C(O)NR^(e)R^(e), NR^(e)C(O)OR^(e), C(═NR^(e))NR^(e)R^(e), NR^(e)C(═NR^(e))NR^(e)R^(e), NR^(e)C(═NOH)NR^(e)R^(e), NR^(e)C(═NCN)NR^(e)R^(e), S(O)R^(e), S(O)NR^(e)R^(e), S(O)₂R^(e), NR^(e)S(O)₂R^(e), NR^(e)S(O)₂NR^(e)R^(e), or S(O)₂NR^(e)R^(e), wherein the C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are optionally substituted with 1, 2, or 3 R^(f) substituents; R^(f) is selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, halogen, CN, NHOR^(g), OR^(g), SR^(g), C(O)R^(g), C(O)NR^(g)R^(g), C(O)OR^(g), OC(O)R^(g), OC(O)NR^(g)R^(g), NHR^(g), NR^(g)R^(g), NR^(g)C(O)R^(g), NR^(g)C(O)NR^(g)R^(g), NR^(g)C(O)OR^(g), C(═NR^(g))NR^(g)R^(g), NR^(g)C(═NR^(g))NR^(g)R^(g), S(O)R^(g), S(O)NR^(g)R^(g), S(O)₂R^(g), NR^(g)S(O)₂R^(g), NR^(g)S(O)₂NR^(g)R^(g), or S(O)₂NR^(g)R^(g); wherein the C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are optionally substituted with 1, 2, 3, 4, or 5 R^(n) substituents; R^(g) is selected from hydrogen, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, or (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are optionally substituted with 1, 2, or 3 R^(p) substituents; R^(n) is selected from cyano, halo, C₁₋₄ alkyl, C₃₋₁₀ cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-6 membered heteroaryl)-C₁₋₄ alkyl-, (4-7 membered heterocycloalkyl)-C₁₋₄ alkyl-, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl, R^(o), NHOR^(o), OR^(o), SR^(o), C(O)R^(o), C(O)NR^(o)R^(o), C(O)OR^(o), OC(O)R^(o), OC(O)NR^(o)R^(o), NHR^(o), NR^(o)R^(o), NR^(o)C(O)R^(o), NR^(o)C(O)NR^(o)R^(o), NR^(o)C(O)OR^(o), C(═NR)NR^(o)R^(o), NR^(o)C(═NR^(o))NR^(o)R^(o), S(O)R^(o), S(O)NR^(o)R^(o), S(O)₂R^(o), NR^(o)S(O)₂R^(o), NR^(o)S(O)₂NR^(o)R^(o), or S(O)₂NR^(o)R^(o), wherein the C₁₋₄ alkyl, C₃₋₁₀ cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-6 membered heteroaryl)-C₁₋₄ alkyl-, (4-7 membered heterocycloalkyl)-C₁₋₄ alkyl-, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₄ haloalkyl are optionally substituted with 1, 2 or 3 R^(q) substituents; R^(p) is selected from halo, cyano, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, NHOR^(r), OR^(r), SR^(r), C(O)R^(r), C(O)NR^(r)R^(r), C(O)OR^(r), OC(O)R^(r), OC(O)NR^(r)R^(r), NHR^(r), NR^(r)R^(r), NR^(r)C(O)R^(r), NR^(r)C(O)NR^(r)R^(r), NR^(r)C(O)OR^(r), C(═NR^(r))NR^(r)R^(r), NR^(r)C(═NR^(r))NR^(r)R^(r), NR^(r)C(═NOH)NR^(r)R^(r), NR^(r)C(═NCN)NR^(r)R^(r), S(O)R^(r), S(O)NR^(r)R^(r), S(O)₂R^(r), NR^(r)S(O)₂R^(r), NR^(r)S(O)₂NR^(r)R^(r) or S(O)₂NR^(r)R^(r), wherein the C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are optionally substituted with 1, 2 or 3 R^(q) substituents; R^(e), R^(i), R^(k), R^(o) and R^(r) are independently selected from hydrogen, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5 or 6-membered heteroaryl, 4-6 membered heterocycloalkyl, C₁₋₄ haloalkyl, C₂₋₄ alkenyl, or C₂₋₄ alkynyl, wherein the C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5 or 6-membered heteroaryl, 4-6 membered heterocycloalkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl are optionally substituted with 1, 2 or 3 R^(q) substituents; R^(q) is selected from hydroxy, cyano, amino, halo, COOH, C₁₋₆ haloalkyl, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylthio, C₅₋₆ aryl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, C₃₋₆ cycloalkyl, NHR⁸, NR⁸R⁸, and C₁₋₄ haloalkoxy, wherein the C₁₋₆ alkyl, C₅₋₆ aryl, C₃₋₆ cycloalkyl, 4-6 membered heterocycloalkyl, and 5-6 membered heteroaryl are optionally substituted with halo, hydroxy, cyano, COOH, amino, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₅₋₆ aryl, C₃₋₁₀ cycloalkyl, 5-6 membered heteroaryl and 4-6 membered heterocycloalkyl; R⁸ is C₁₋₆ alkyl; m is 1 or 2; Ring A is selected from substituted or unsubstituted C₅₋₁₀ aryl, substituted or unsubstituted C₃₋₆ cycloalkyl, and substituted or unsubstituted 6-10 membered monocyclic saturated or unsaturated heterocyclic ring with 1-3 heteroatoms selected from N, S or O; Ring B is selected from C₅₋₁₀ aryl, C₃₋₆ cycloalkyl, 5-10 membered monocyclic saturated or unsaturated heterocyclic ring with 1-3 heteroatoms selected from N, S or O.
 2. The compound as claimed in claim 1 having the structure of Formula II

their polymorphs, stereoisomers, tautomers, prodrugs, solvates, and pharmaceutically acceptable salts thereof, wherein X₁ is selected from —CH₂O—, —OCH₂—, —C(O)NH— or —NHC(O)—; R₄ is selected from hydrogen, C₁₋₆ alkyl, —C(O)OR_(a1), C(O)NR_(b1)R_(c1), C₅₋₆ aryl, or C₁₋₆ heteroaryl, wherein C₁₋₆ alkyl is optionally substituted with one or more of the groups selected from the group consisting of hydrogen, hydroxyl, amino, —C(O)OR_(a1), C(O)NR_(b1)R_(c1), C₅₋₆ aryl, and C₁₋₆ heteroaryl; R_(a1), R_(b1), and R_(c1) are independently selected from hydrogen or C₁₋₆ alkyl; R₅ is selected from C₁₋₄ alkyl, cyano, or C₁₋₄ haloalkyl; R₁, R₂, R₃, R₆, and R₇ are independently selected from hydrogen, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-14 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a), SR^(a), NHOR^(a), C(O)R^(a), C(O)NR^(a)R^(a), C(O)OR^(a), OC(O)R^(a), OC(O)NR^(a)R^(a), NHR^(a), NR^(a)R^(a), NR^(a)C(O)R^(a), NR^(a)C(O)OR^(a), NR^(a)C(O)NR^(a)R^(a), C(═NR^(a))R^(a), C(═NR^(a))NR^(a)R^(a), NR^(a)C(═NR^(a))NR^(a)R^(a), NR^(a)S(O)R^(a), NR^(a)S(O)₂R^(a), NR^(a)S(O)₂NR^(a)R^(a), S(O)R^(a), S(O)NR^(a)R^(a), S(O)₂R^(a), or S(O)₂NR^(a)R^(a), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-14 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, are independently optionally substituted with 1, 2, 3, or 4 R^(b) substituents; R^(a) is selected from hydrogen, cyano, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, or (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are independently optionally substituted with 1, 2, 3, 4, or 5 R^(d) substituents; R^(b) is selected from halo, hydroxy, cyano, amino, nitro, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, NHOR^(c), OR^(c), SR^(c), C(O)R^(c), C(O)NR^(c)R^(c), C(O)OR^(c), OC(O)R^(c), OC(O)NR^(c)R^(c), C(═NR^(c))NR^(c)R^(c), NR^(c)C(═NR^(c))NR^(c)R^(c), NHR^(c), NR^(c)R^(c), NR^(c)C(O)R^(c), NR^(c)C(O)OR^(c), NR^(c)C(O)NR^(c)R^(c), NR^(c)S(O)R^(c), NR^(c)S(O)₂R^(c), NR^(c)S(O)₂NR^(c)R^(c), S(O)R^(c), S(O)NR^(c)R^(c), S(O)₂R^(c) or S(O)₂NR^(c)R^(c); wherein the C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are optionally substituted with 1, 2, or 3 R^(d) substituents; R^(d) is selected from cyano, amino, C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, NHOR^(e), OR^(e), SR^(e), C(O)R^(e), C(O)NR^(e)R^(e), C(O)OR^(e), OC(O)R^(e), OC(O)NR^(e)R^(e), NHR^(e), NR^(e)R^(e), NR^(e)C(O)R^(e), NR^(e)C(O)NR^(e)R^(e), NR^(e)C(O)OR^(e), C(═NR^(e))NR^(e)R^(e), NR^(e)C(═NR^(e))NR^(e)R^(e), NR^(e)C(═NOH)NR^(e)R^(e), NR^(e)C(═NCN)NR^(e)R^(e), S(O)R^(e), S(O)NR^(e)R^(e), S(O)₂R^(e), NR^(e)S(O)₂R^(e), NR^(e)S(O)₂NR^(e)R^(e), or S(O)₂NR^(e)R^(e), wherein the C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are optionally substituted with 1, 2, or 3 R^(f) substituents; R^(c) is selected from hydrogen, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, or (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are optionally substituted with 1, 2, 3, 4, or 5 R^(f) substituent; R^(f) is selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, halogen, CN, NHOR^(g), R^(g), SR^(g), C(O)R^(g), C(O)NR^(g)R^(g), C(O)OR^(g), OC(O)R^(g), OC(O)NR^(g)R^(g), NHR^(g), NR^(g)R^(g), NR^(g)C(O)R^(g), NR^(g)C(O)NR^(g)R^(g), NR^(g)C(O)OR^(g), C(═NR^(g))NR^(g)R^(g), NR^(g)C(═NR^(g))NR^(g)R^(g), S(O)R^(g), S(O)NR^(g)R^(g), S(O)₂R^(g), NR^(g)S(O)₂R^(g), NR^(g)S(O)₂NR^(g)R^(g), or S(O)₂NR^(g)R^(g); wherein the C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are optionally substituted with 1, 2, 3, 4, or 5 R^(n) substituents; R^(n) is selected from cyano, halo, C₁₋₄ alkyl, C₃₋₁₀ cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-6 membered heteroaryl)-C₁₋₄ alkyl-, (4-7 membered heterocycloalkyl)-C₁₋₄ alkyl-, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl, R^(o), NHOR^(o), OR^(o), SR^(o), C(O)R^(o), C(O)NR^(o)R^(o), C(O)OR^(o), OC(O)R^(o), OC(O)NR^(o)R^(o), NHR^(o), NR^(o)R^(o), NR^(o)C(O)R^(o), NR^(o)C(O)NR^(o)R^(o), NR^(o)C(O)OR^(o), C(═NR)NR^(o)R^(o), NR^(o)C(═NR^(o))NR^(o)R^(o), S(O)R^(o), S(O)NR^(o)R^(o), S(O)₂R^(o), NR^(o)S(O)₂R^(o), NR^(o)S(O)₂NR^(o)R^(o), or S(O)₂NR^(o)R^(o), wherein the C₁₋₄ alkyl, C₃₋₁₀ cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-6 membered heteroaryl)-C₁₋₄ alkyl-, (4-7 membered heterocycloalkyl)-C₁₋₄ alkyl-, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₄ haloalkyl are optionally substituted with 1, 2 or 3 R^(q) substituents; R^(g) is selected from hydrogen, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, or (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are optionally substituted with 1, 2, or 3 R^(p) substituents; R^(p) is selected from halo, cyano, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, NHOR^(r), OR^(r), SR^(r), C(O)R^(r), C(O)NR^(r)R^(r), C(O)OR^(r), OC(O)R^(r), OC(O)NR^(r)R^(r), NHR^(r), NR^(r)R^(r), NR^(r)C(O)R^(r), NR^(r)C(O)NR^(r)R^(r), NR^(r)C(O)OR^(r), C(═NR^(r))NR^(r)R^(r), NR^(r)C(═NR^(r))NR^(r)R^(r), NR^(r)C(═NOH)NR^(r)R^(r), NR^(r)C(═NCN)NR^(r)R^(r), S(O)R^(r), S(O)NR^(r)R^(r), S(O)₂R^(r), NR^(r)S(O)₂R^(r), NR^(r)S(O)₂NR^(r)R^(r) or S(O)₂NR^(r)R^(r), wherein the C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are optionally substituted with 1, 2 or 3 R^(q) substituents; R^(e), R^(i), R^(k), R^(o) and R^(r) are independently selected from hydrogen, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5 or 6-membered heteroaryl, 4-6 membered heterocycloalkyl, C₁₋₄ haloalkyl, C₂₋₄ alkenyl, or C₂₋₄ alkynyl, wherein the C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5 or 6-membered heteroaryl, 4-6 membered heterocycloalkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl are optionally substituted with 1, 2 or 3 R^(q) substituents; R^(q) is selected from hydroxy, cyano, amino, halo, COOH, C₁₋₆ haloalkyl, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylthio, C₅₋₆ aryl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, C₃₋₆ cycloalkyl, NHR⁸, NR⁸R⁸, and C₁₋₄ haloalkoxy, wherein the C₁₋₆ alkyl, C₅₋₆ aryl, C₃₋₆ cycloalkyl, 4-6 membered heterocycloalkyl, and 5-6 membered heteroaryl are optionally substituted with halo, hydroxy, cyano, COOH, amino, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₅₋₆ aryl, C₃₋₁₀ cycloalkyl, 5-6 membered heteroaryl and 4-6 membered heterocycloalkyl; R⁸ is C₁₋₆ alkyl; Ring B is selected from C₅₋₁₀ aryl, C₃₋₆ cycloalkyl, 5-10 membered monocyclic saturated or unsaturated heterocyclic ring with 1-3 heteroatoms selected from N, S or O.
 3. The compound as claimed in claim 1 having the structure of Formula III

their polymorphs, stereoisomers, tautomers, prodrugs, solvates, and pharmaceutically acceptable salts thereof, wherein X₁ is selected from —CH₂O—, —OCH₂—, —C(O)NH— or —NHC(O)—; R₄ is selected from hydrogen, C₁₋₆ alkyl, —C(O)OR_(a1), C(O)NR_(b1)R_(c1), C₅₋₆ aryl, or C₁₋₆ heteroaryl; wherein C₁₋₆ alkyl is optionally substituted with one or more of the groups selected from the group consisting of hydrogen, hydroxyl, amino, —C(O)OR_(a1), C(O)NR_(b1)R_(c1), C₅₋₆ aryl, and C₁₋₆ heteroaryl; R_(a1), R_(b1), and R_(c1) are independently selected from hydrogen or C₁₋₆ alkyl; R₅ is selected from C₁₋₄ alkyl, cyano, or C₁₋₄ haloalkyl; R₁, R₂, R₃, R₆, and R₇ are independently selected from hydrogen, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-14 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a), SR^(a), NHOR^(a), C(O)R^(a), C(O)NR^(a)R^(a), C(O)OR^(a), OC(O)R^(a), OC(O)NR^(a)R^(a), NHR^(a), NR^(a)R^(a), NR^(a)C(O)R^(a), NR^(a)C(O)OR^(a), NR^(a)C(O)NR^(a)R^(a), C(═NR^(a))R^(a), C(═NR^(a))NR^(a)R^(a), NR^(a)C(═NR^(a))NR^(a)R^(a), NR^(a)S(O)R^(a), NR^(a)S(O)₂R^(a), NR^(a)S(O)₂NR^(a)R^(a), S(O)R^(a), S(O)NR^(a)R^(a), S(O)₂R^(a), or S(O)₂NR^(a)R^(a), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-14 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, are independently optionally substituted with 1, 2, 3, or 4 R^(b) substituents; R^(a) is selected from hydrogen, cyano, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, or (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are independently optionally substituted with 1, 2, 3, 4, or 5 R^(d) substituents; R^(b) is selected from halo, hydroxy, cyano, amino, nitro, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁_₄ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, NHOR^(c), OR^(c), SR^(c), C(O)R^(c), C(O)NR^(c)R^(c), C(O)OR^(c), OC(O)R^(c), OC(O)NR^(c)R^(c), C(═NR^(c))NR^(c)R^(c), NR^(c)C(═NR^(c))NR^(c)R^(c), NHR^(c), NR^(c)R^(c), NR^(c)C(O)R^(c), NR^(c)C(O)OR^(c), NR^(c)C(O)NR^(c)R^(c), NR^(c)S(O)R^(c), NR^(c)S(O)₂R^(c), NR^(c)S(O)₂NR^(c)R^(c), S(O)R^(c), S(O)NR^(c)R^(c), S(O)₂R^(c) or S(O)₂NR^(c)R^(c); wherein the C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are optionally substituted with 1, 2, or 3 R^(d) substituents; R^(d) is selected from cyano, amino, C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, NHOR^(e), OR^(e), SR^(e), C(O)R^(e), C(O)NR^(e)R^(e), C(O)OR^(e), OC(O)R^(e), OC(O)NR^(e)R^(e), NHR^(e), NR^(e)R^(e), NR^(e)C(O)R^(e), NR^(e)C(O)NR^(e)R^(e), NR^(e)C(O)OR^(e), C(═NR^(e))NR^(e)R^(e), NR^(e)C(═NR^(e))NR^(e)R^(e), NR^(e)C(═NOH)NR^(e)R^(e), NR^(e)C(═NCN)NR^(e)R^(e), S(O)R^(e), S(O)NR^(e)R^(e), S(O)₂R^(e), NR^(e)S(O)₂R^(e), NR^(e)S(O)₂NR^(e)R^(e), or S(O)₂NR^(e)R^(e), wherein the C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are optionally substituted with 1, 2, or 3 R^(f) substituents; R^(c) is selected from hydrogen, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, or (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are optionally substituted with 1, 2, 3, 4, or 5 R^(f) substituent; R^(f) is selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, halogen, CN, NHOR^(g), R^(g), SR^(g), C(O)R^(g), C(O)NR^(g)R^(g), C(O)OR^(g), OC(O)R^(g), OC(O)NR^(g)R^(g), NHR^(g), NR^(g)R^(g), NR^(g)C(O)R^(g), NR^(g)C(O)NR^(g)R^(g), NR^(g)C(O)OR^(g), C(═NR^(g))NR^(g)R^(g), NR^(g)C(═NR^(g))NR^(g)R^(g), S(O)R^(g), S(O)NR^(g)R^(g), S(O)₂R^(g), NR^(g)S(O)₂R^(g), NR^(g)S(O)₂NR^(g)R^(g), or S(O)₂NR^(g)R^(g); wherein the C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are optionally substituted with 1, 2, 3, 4, or 5 R^(n) substituents; R^(n) is selected from cyano, halo, C₁₋₄ alkyl, C₃₋₁₀ cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-6 membered heteroaryl)-C₁₋₄ alkyl-, (4-7 membered heterocycloalkyl)-C₁₋₄ alkyl-, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl, R^(o), NHOR^(o), OR^(o), SR^(o), C(O)R^(o), C(O)NR^(o)R^(o), C(O)OR^(o), OC(O)R^(o), OC(O)NR^(o)R^(o), NHR^(o), NR^(o)R^(o), NR^(o)C(O)R^(o), NR^(o)C(O)NR^(o)R^(o), NR^(o)C(O)OR^(o), C(═NR)NR^(o)R^(o), NR^(o)C(═NR^(o))NR^(o)R^(o), S(O)R^(o), S(O)NR^(o)R^(o), S(O)₂R^(o), NR^(o)S(O)₂R^(o), NR^(o)S(O)₂NR^(o)R^(o), or S(O)₂NR^(o)R^(o), wherein the C₁₋₄ alkyl, C₃₋₁₀ cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-6 membered heteroaryl)-C₁₋₄ alkyl-, (4-7 membered heterocycloalkyl)-C₁₋₄ alkyl-, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₄ haloalkyl are optionally substituted with 1, 2 or 3 R^(q) substituents; R^(g) is selected from hydrogen, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, or (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are optionally substituted with 1, 2, or 3 R^(p) substituents; R^(p) is selected from halo, cyano, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, NHOR^(r), OR^(r), SR^(r), C(O)R^(r), C(O)NR^(r)R^(r), C(O)OR^(r), OC(O)R^(r), OC(O)NR^(r)R^(r), NHR^(r), NR^(r)R^(r), NR^(r)C(O)R^(r), NR^(r)C(O)NR^(r)R^(r), NR^(r)C(O)OR^(r), C(═NR^(r))NR^(r)R^(r), NR^(r)C(═NR^(r))NR^(r)R^(r), NR^(r)C(═NOH)NR^(r)R^(r), NR^(r)C(═NCN)NR^(r)R^(r), S(O)R^(r), S(O)NR^(r)R^(r), S(O)₂R^(r), NR^(r)S(O)₂R^(r), NR^(r)S(O)₂NR^(r)R^(r) or S(O)₂NR^(r)R^(r), wherein the C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are optionally substituted with 1, 2 or 3 R^(q) substituents; R^(e), R^(i), R^(k), R^(o) and R^(r) are independently selected from hydrogen, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5 or 6-membered heteroaryl, 4-6 membered heterocycloalkyl, C₁₋₄ haloalkyl, C₂₋₄ alkenyl, or C₂₋₄ alkynyl, wherein the C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5 or 6-membered heteroaryl, 4-6 membered heterocycloalkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl are optionally substituted with 1, 2 or 3 R^(q) substituents; R^(q) is selected from hydroxy, cyano, amino, halo, COOH, C₁₋₆ haloalkyl, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylthio, C₅₋₆ aryl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, C₃₋₆ cycloalkyl, NHR⁸, NR⁸R⁸, and C₁₋₄ haloalkoxy, wherein the C₁₋₆ alkyl, C₅₋₆ aryl, C₃₋₆ cycloalkyl, 4-6 membered heterocycloalkyl, and 5-6 membered heteroaryl are optionally substituted with halo, hydroxy, cyano, COOH, amino, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₅₋₆ aryl, C₃₋₁₀ cycloalkyl, 5-6 membered heteroaryl and 4-6 membered heterocycloalkyl; R⁸ is C₁₋₆ alkyl.
 4. The compound as claimed in claim 1 having the structure of Formula IV

their polymorphs, stereoisomers, tautomers, prodrugs, solvates, and pharmaceutically acceptable salts thereof, wherein R₅ is selected from C₁₋₄ alkyl, cyano, or C₁₋₄ haloalkyl; R₁, R₂, R₃, R₆, and R₇ are independently selected from hydrogen, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-14 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a), SR^(a), NHOR^(a), C(O)R^(a), C(O)NR^(a)R^(a), C(O)OR^(a), OC(O)R^(a), OC(O)NR^(a)R^(a), NHR^(a), NR^(a)R^(a), NR^(a)C(O)R^(a), NR^(a)C(O)OR^(a), NR^(a)C(O)NR^(a)R^(a), C(═NR^(a))R^(a), C(═NR^(a))NR^(a)R^(a), NR^(a)C(═NR^(a))NR^(a)R^(a), NR^(a)S(O)R^(a), NR^(a)S(O)₂R^(a), NR^(a)S(O)₂NR^(a)R^(a), S(O)R^(a), S(O)NR^(a)R^(a), S(O)₂R^(a), or S(O)₂NR^(a)R^(a), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-14 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, are independently optionally substituted with 1, 2, 3, or 4 R^(b) substituents; R^(a) is selected from hydrogen, cyano, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, or (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are independently optionally substituted with 1, 2, 3, 4, or 5 R^(d) substituents; R^(b) is selected from halo, hydroxy, cyano, amino, nitro, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, NHOR^(c), OR^(c), SR^(c), C(O)R^(c), C(O)NR^(c)R^(c), C(O)OR^(c), OC(O)R^(c), OC(O)NR^(c)R^(c), C(═NR^(c))NR^(c)R^(c), NR^(c)C(═NR^(c))NR^(c)R^(c), NHR^(c), NR^(c)R^(c), NR^(c)C(O)R^(c), NR^(c)C(O)OR^(c), NR^(c)C(O)NR^(c)R^(c), NR^(c)S(O)R^(c), NR^(c)S(O)₂R^(c), NR^(c)S(O)₂NR^(c)R^(c), S(O)R^(c), S(O)NR^(c)R^(c), S(O)₂R^(c) or S(O)₂NR^(c)R^(c); wherein the C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are optionally substituted with 1, 2, or 3 R^(d) substituents; R^(d) is selected from cyano, amino, C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, NHOR^(e), OR^(e), SR^(e), C(O)R^(e), C(O)NR^(e)R^(e), C(O)OR^(e), OC(O)R^(e), OC(O)NR^(e)R^(e), NHR^(e), NR^(e)R^(e), NR^(e)C(O)R^(e), NR^(e)C(O)NR^(e)R^(e), NR^(e)C(O)OR^(e), C(═NR^(e))NR^(e)R^(e), NR^(e)C(═NR^(e))NR^(e)R^(e), NR^(e)C(═NOH)NR^(e)R^(e), NR^(e)C(═NCN)NR^(e)R^(e), S(O)R^(e), S(O)NR^(e)R^(e), S(O)₂R^(e), NR^(e)S(O)₂R^(e), NR^(e)S(O)₂NR^(e)R^(e), or S(O)₂NR^(e)R^(e), wherein the C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are optionally substituted with 1, 2, or 3 R^(f) substituents; R^(c) is selected from hydrogen, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, or (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are optionally substituted with 1, 2, 3, 4, or 5 R^(f) substituent; R^(f) is selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, halogen, CN, NHOR^(g), R^(g), SR^(g), C(O)R^(g), C(O)NR^(g)R^(g), C(O)OR^(g), OC(O)R^(g), OC(O)NR^(g)R^(g), NHR^(g), NR^(g)R^(g), NR^(g)C(O)R^(g), NR^(g)C(O)NR^(g)R^(g), NR^(g)C(O)OR^(g), C(═NR^(g))NR^(g)R^(g), NR^(g)C(═NR^(g))NR^(g)R^(g), S(O)R^(g), S(O)NR^(g)R^(g), S(O)₂R^(g), NR^(g)S(O)₂R^(g), NR^(g)S(O)₂NR^(g)R^(g), or S(O)₂NR^(g)R^(g); wherein the C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are optionally substituted with 1, 2, 3, 4, or 5 R^(n) substituents; R^(n) is selected from cyano, halo, C₁₋₄ alkyl, C₃₋₁₀ cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-6 membered heteroaryl)-C₁₋₄ alkyl-, (4-7 membered heterocycloalkyl)-C₁₋₄ alkyl-, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl, R^(o), NHOR^(o), OR^(o), SR^(o), C(O)R^(o), C(O)NR^(o)R^(o), C(O)OR^(o), OC(O)R^(o), OC(O)NR^(o)R^(o), NHR^(o), NR^(o)R^(o), NR^(o)C(O)R^(o), NR^(o)C(O)NR^(o)R^(o), NR^(o)C(O)OR^(o), C(═NR)NR^(o)R^(o), NR^(o)C(═NR^(o))NR^(o)R^(o), S(O)R^(o), S(O)NR^(o)R^(o), S(O)₂R^(o), NR^(o)S(O)₂R^(o), NR^(o)S(O)₂NR^(o)R^(o), or S(O)₂NR^(o)R^(o), wherein the C₁₋₄ alkyl, C₃₋₁₀ cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-6 membered heteroaryl)-C₁₋₄ alkyl-, (4-7 membered heterocycloalkyl)-C₁₋₄ alkyl-, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₄ haloalkyl are optionally substituted with 1, 2 or 3 R^(q) substituents; R^(g) is selected from hydrogen, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, or (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are optionally substituted with 1, 2, or 3 R^(p) substituents; R^(p) is selected from halo, cyano, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, NHOR^(r), OR^(r), SR^(r), C(O)R^(r), C(O)NR^(r)R^(r), C(O)OR^(r), OC(O)R^(r), OC(O)NR^(r)R^(r), NHR^(r), NR^(r)R^(r), NR^(r)C(O)R^(r), NR^(r)C(O)NR^(r)R^(r), NR^(r)C(O)OR^(r), C(═NR^(r))NR^(r)R^(r), NR^(r)C(═NR^(r))NR^(r)R^(r), NR^(r)C(═NOH)NR^(r)R^(r), NR^(r)C(═NCN)NR^(r)R^(r), S(O)R^(r), S(O)NR^(r)R^(r), S(O)₂R^(r), NR^(r)S(O)₂R^(r), NR^(r)S(O)₂NR^(r)R^(r) or S(O)₂NR^(r)R^(r), wherein the C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are optionally substituted with 1, 2 or 3 R^(q) substituents; R^(e), R^(i), R^(k), R^(o) and R^(r) are independently selected from hydrogen, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5 or 6-membered heteroaryl, 4-6 membered heterocycloalkyl, C₁₋₄ haloalkyl, C₂₋₄ alkenyl, or C₂₋₄ alkynyl, wherein the C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5 or 6-membered heteroaryl, 4-6 membered heterocycloalkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl are optionally substituted with 1, 2 or 3 R^(q) substituents; R^(q) is selected from hydroxy, cyano, amino, halo, COOH, C₁₋₆ haloalkyl, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylthio, C₅₋₆ aryl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, C₃₋₆ cycloalkyl, NHR⁸, NR⁸R⁸, and C₁₋₄ haloalkoxy, wherein the C₁₋₆ alkyl, C₅₋₆ aryl, C₃₋₆ cycloalkyl, 4-6 membered heterocycloalkyl, and 5-6 membered heteroaryl are optionally substituted with halo, hydroxy, cyano, COOH, amino, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₅₋₆ aryl, C₃₋₁₀ cycloalkyl, 5-6 membered heteroaryl and 4-6 membered heterocycloalkyl; R⁸ is C₁₋₆ alkyl.
 5. The compound as claimed in claim 1 having the structure of Formula V

their polymorphs, stereoisomers, tautomers, prodrugs, solvates, and pharmaceutically acceptable salts thereof, wherein R₅ is selected from C₁₋₄ alkyl, cyano, or C₁₋₄ haloalkyl; R₄ is selected from hydrogen, C₁₋₆ alkyl, —C(O)OR_(a1), C(O)NR_(b1)R_(c1), C₅₋₆ aryl, or C₁₋₆ heteroaryl; wherein C₁₋₆ alkyl is optionally substituted with one or more of the groups selected from the group consisting of hydrogen, hydroxyl, amino, —C(O)OR_(a1), C(O)NR_(b1)R_(c1), C₅₋₆ aryl, and C₁₋₆ heteroaryl; R_(a1), R_(b1), and R_(c1) are independently selected from hydrogen or C₁₋₆ alkyl; R₁, R₂, R₃, R₆, and R₇ are independently selected from hydrogen, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-14 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a), SR^(a), NHOR^(a), C(O)R^(a), C(O)NR^(a)R^(a), C(O)OR^(a), OC(O)R^(a), OC(O)NR^(a)R^(a), NHR^(a), NR^(a)R^(a), NR^(a)C(O)R^(a), NR^(a)C(O)OR^(a), NR^(a)C(O)NR^(a)R^(a), C(═NR^(a))R^(a), C(═NR^(a))NR^(a)R^(a), NR^(a)C(═NR^(a))NR^(a)R^(a), NR^(a)S(O)R^(a), NR^(a)S(O)₂R^(a), NR^(a)S(O)₂NR^(a)R^(a), S(O)R^(a), S(O)NR^(a)R^(a), S(O)₂R^(a), or S(O)₂NR^(a)R^(a), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-14 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, are independently optionally substituted with 1, 2, 3, or 4 R^(b) substituents; R^(a) is selected from hydrogen, cyano, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, or (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are independently optionally substituted with 1, 2, 3, 4, or 5 R^(d) substituents; R^(b) is selected from halo, hydroxy, cyano, amino, nitro, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, NHOR^(c), OR^(c), SR^(c), C(O)R^(c), C(O)NR^(c)R^(c), C(O)OR^(c), OC(O)R^(c), OC(O)NR^(c)R^(c), C(═NR^(c))NR^(c)R^(c), NR^(c)C(═NR^(c))NR^(c)R^(c), NHR^(c), NR^(c)R^(c), NR^(c)C(O)R^(c), NR^(c)C(O)OR^(c), NR^(c)C(O)NR^(c)R^(c), NR^(c)S(O)R^(c), NR^(c)S(O)₂R^(c), NR^(c)S(O)₂NR^(c)R^(c), S(O)R^(c), S(O)NR^(c)R^(c), S(O)₂R^(c) or S(O)₂NR^(c)R^(c); wherein the C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are optionally substituted with 1, 2, or 3 R^(d) substituents; R^(d) is selected from cyano, amino, C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, NHOR^(e), OR^(e), SR^(e), C(O)R^(e), C(O)NR^(e)R^(e), C(O)OR^(e), OC(O)R^(e), OC(O)NR^(e)R^(e), NHR^(e), NR^(e)R^(e), NR^(e)C(O)R^(e), NR^(e)C(O)NR^(e)R^(e), NR^(e)C(O)OR^(e), C(═NR^(e))NR^(e)R^(e), NR^(e)C(═NR^(e))NR^(e)R^(e), NR^(e)C(═NOH)NR^(e)R^(e), NR^(e)C(═NCN)NR^(e)R^(e), S(O)R^(e), S(O)NR^(e)R^(e), S(O)₂R^(e), NR^(e)S(O)₂R^(e), NR^(e)S(O)₂NR^(e)R^(e), or S(O)₂NR^(e)R^(e), wherein the C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are optionally substituted with 1, 2, or 3 R^(f) substituents; R^(c) is selected from hydrogen, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, or (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are optionally substituted with 1, 2, 3, 4, or 5 R^(f) substituent; R^(f) is selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, halogen, CN, NHOR^(g), R^(g), SR^(g), C(O)R^(g), C(O)NR^(g)R^(g), C(O)OR^(g), OC(O)R^(g), OC(O)NR^(g)R^(g), NHR^(g), NR^(g)R^(g), NR^(g)C(O)R^(g), NR^(g)C(O)NR^(g)R^(g), NR^(g)C(O)OR^(g), C(═NR^(g))NR^(g)R^(g), NR^(g)C(═NR^(g))NR^(g)R^(g), S(O)R^(g), S(O)NR^(g)R^(g), S(O)₂R^(g), NR^(g)S(O)₂R^(g), NR^(g)S(O)₂NR^(g)R^(g), or S(O)₂NR^(g)R^(g); wherein the C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are optionally substituted with 1, 2, 3, 4, or 5 R^(n) substituents; R^(n) is selected from cyano, halo, C₁₋₄ alkyl, C₃₋₁₀ cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-6 membered heteroaryl)-C₁₋₄ alkyl-, (4-7 membered heterocycloalkyl)-C₁₋₄ alkyl-, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl, R^(o), NHOR^(o), OR^(o), SR^(o), C(O)R^(o), C(O)NR^(o)R^(o), C(O)OR^(o), OC(O)R^(o), OC(O)NR^(o)R^(o), NHR^(o), NR^(o)R^(o), NR^(o)C(O)R^(o), NR^(o)C(O)NR^(o)R^(o), NR^(o)C(O)OR^(o), C(═NR)NR^(o)R^(o), NR^(o)C(═NR^(o))NR^(o)R^(o), S(O)R^(o), S(O)NR^(o)R^(o), S(O)₂R^(o), NR^(o)S(O)₂R^(o), NR^(o)S(O)₂NR^(o)R^(o), or S(O)₂NR^(o)R^(o), wherein the C₁₋₄ alkyl, C₃₋₁₀ cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-6 membered heteroaryl)-C₁₋₄ alkyl-, (4-7 membered heterocycloalkyl)-C₁₋₄ alkyl-, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₄ haloalkyl are optionally substituted with 1, 2 or 3 R^(q) substituents; R^(g) is selected from hydrogen, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, or (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are optionally substituted with 1, 2, or 3 R^(p) substituents; R^(p) is selected from halo, cyano, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, NHOR^(r), OR^(r), SR^(r), C(O)R^(r), C(O)NR^(r)R^(r), C(O)OR^(r), OC(O)R^(r), OC(O)NR^(r)R^(r), NHR^(r), NR^(r)R^(r), NR^(r)C(O)R^(r), NR^(r)C(O)NR^(r)R^(r), NR^(r)C(O)OR^(r), C(═NR^(r))NR^(r)R^(r), NR^(r)C(═NR^(r))NR^(r)R^(r), NR^(r)C(═NOH)NR^(r)R^(r), NR^(r)C(═NCN)NR^(r)R^(r), S(O)R^(r), S(O)NR^(r)R^(r), S(O)₂R^(r), NR^(r)S(O)₂R^(r), NR^(r)S(O)₂NR^(r)R^(r) or S(O)₂NR^(r)R^(r), wherein the C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are optionally substituted with 1, 2 or 3 R^(q) substituents; R^(e), R^(i), R^(k), R^(o) and R^(r) are independently selected from hydrogen, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5 or 6-membered heteroaryl, 4-6 membered heterocycloalkyl, C₁₋₄ haloalkyl, C₂₋₄ alkenyl, or C₂₋₄ alkynyl, wherein the C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5 or 6-membered heteroaryl, 4-6 membered heterocycloalkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl are optionally substituted with 1, 2 or 3 R^(q) substituents; R^(q) is selected from hydroxy, cyano, amino, halo, COOH, C₁₋₆ haloalkyl, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylthio, C₅₋₆ aryl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, C₃₋₆ cycloalkyl, NHR⁸, NR⁸R⁸, and C₁₋₄ haloalkoxy, wherein the C₁₋₆ alkyl, C₅₋₆ aryl, C₃₋₆ cycloalkyl, 4-6 membered heterocycloalkyl, and 5-6 membered heteroaryl are optionally substituted with halo, hydroxy, cyano, COOH, amino, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₅₋₆ aryl, C₃₋₁₀ cycloalkyl, 5-6 membered heteroaryl and 4-6 membered heterocycloalkyl; R⁸ is C₁₋₆ alkyl.
 6. The compound as claimed in claim 1 having the structure of Formula VI

their polymorphs, stereoisomers, tautomers, prodrugs, solvates, and pharmaceutically acceptable salts thereof, wherein R₅ is selected from C₁₋₄ alkyl, cyano, or C₁₋₄ haloalkyl; R₄ is selected from hydrogen, C₁₋₆ alkyl, —C(O)OR_(a1), C(O)NR_(b1)R_(c1), C₅₋₆ aryl, or C₁₋₆ heteroaryl; wherein C₁₋₆ alkyl is optionally substituted with one or more of the groups selected from the group consisting of hydrogen, hydroxyl, amino, —C(O)OR_(a1), C(O)NR_(b1)R_(c1), C₅₋₆ aryl, and C₁₋₆ heteroaryl; R_(a1), R_(b1), and R_(c1) are independently selected from hydrogen or C₁₋₆ alkyl; R₁, R₂, R₃, R₆, and R₇ are independently selected from hydrogen, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-14 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a), SR^(a), NHOR^(a), C(O)R^(a), C(O)NR^(a)R^(a), C(O)OR^(a), OC(O)R^(a), OC(O)NR^(a)R^(a), NHR^(a), NR^(a)R^(a), NR^(a)C(O)R^(a), NR^(a)C(O)OR^(a), NR^(a)C(O)NR^(a)R^(a), C(═NR^(a))R^(a), C(═NR^(a))NR^(a)R^(a), NR^(a)C(═NR^(a))NR^(a)R^(a), NR^(a)S(O)R^(a), NR^(a)S(O)₂R^(a), NR^(a)S(O)₂NR^(a)R^(a), S(O)R^(a), S(O)NR^(a)R^(a), S(O)₂R^(a), or S(O)₂NR^(a)R^(a), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-14 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, are independently optionally substituted with 1, 2, 3, or 4 R^(b) substituents; R^(a) is selected from hydrogen, cyano, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, or (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are independently optionally substituted with 1, 2, 3, 4, or 5 R^(d) substituents; R^(b) is selected from halo, hydroxy, cyano, amino, nitro, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁_₄ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, NHOR^(c), OR^(c), SR^(c), C(O)R^(c), C(O)NR^(c)R^(c), C(O)OR^(c), OC(O)R^(c), OC(O)NR^(c)R^(c), C(═NR^(c))NR^(c)R^(c), NR^(c)C(═NR^(c))NR^(c)R^(c), NHR^(c), NR^(c)R^(c), NR^(c)C(O)R^(c), NR^(c)C(O)OR^(c), NR^(c)C(O)NR^(c)R^(c), NR^(c)S(O)R^(c), NR^(c)S(O)₂R^(c), NR^(c)S(O)₂NR^(c)R^(c), S(O)R^(c), S(O)NR^(c)R^(c), S(O)₂R^(c) or S(O)₂NR^(c)R^(c); wherein the C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are optionally substituted with 1, 2, or 3 R^(d) substituents; R^(d) is selected from cyano, amino, C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, NHOR^(e), OR^(e), SR^(e), C(O)R^(e), C(O)NR^(e)R^(e), C(O)OR^(e), OC(O)R^(e), OC(O)NR^(e)R^(e), NHR^(e), NR^(e)R^(e), NR^(e)C(O)R^(e), NR^(e)C(O)NR^(e)R^(e), NR^(e)C(O)OR^(e), C(═NR^(e))NR^(e)R^(e), NR^(e)C(═NR^(e))NR^(e)R^(e), NR^(e)C(═NOH)NR^(e)R^(e), NR^(e)C(═NCN)NR^(e)R^(e), S(O)R^(e), S(O)NR^(e)R^(e), S(O)₂R^(e), NR^(e)S(O)₂R^(e), NR^(e)S(O)₂NR^(e)R^(e), or S(O)₂NR^(e)R^(e), wherein the C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are optionally substituted with 1, 2, or 3 R^(f) substituents; R^(c) is selected from hydrogen, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, or (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are optionally substituted with 1, 2, 3, 4, or 5 R^(f) substituent; R^(f) is selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, halogen, CN, NHOR^(g), OR^(g), SR^(g), C(O)R^(g), C(O)NR^(g)R^(g), C(O)OR^(g), OC(O)R^(g), OC(O)NR^(g)R^(g), NHR^(g), NR^(g)R^(g), NR^(g)C(O)R^(g), NR^(g)C(O)NR^(g)R^(g), NR^(g)C(O)OR^(g), C(═NR^(g))NR^(g)R^(g), NR^(g)C(═NR^(g))NR^(g)R^(g), S(O)R^(g), S(O)NR^(g)R^(g), S(O)₂R^(g), NR^(g)S(O)₂R^(g), NR^(g)S(O)₂NR^(g)R^(g), or S(O)₂NR^(g)R^(g); wherein the C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are optionally substituted with 1, 2, 3, 4, or 5 R^(n) substituents; R^(n) is selected from cyano, halo, C₁₋₄ alkyl, C₃₋₁₀ cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-6 membered heteroaryl)-C₁₋₄ alkyl-, (4-7 membered heterocycloalkyl)-C₁₋₄ alkyl-, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl, R^(o), NHOR^(o), OR^(o), SR^(o), C(O)R^(o), C(O)NR^(o)R^(o), C(O)OR^(o), OC(O)R^(o), OC(O)NR^(o)R^(o), NHR^(o), NR^(o)R^(o), NR^(o)C(O)R^(o), NR^(o)C(O)NR^(o)R^(o), NR^(o)C(O)OR^(o), C(═NR)NR^(o)R^(o), NR^(o)C(═NR^(o))NR^(o)R^(o), S(O)R^(o), S(O)NR^(o)R^(o), S(O)₂R^(o), NR^(o)S(O)₂R^(o), NR^(o)S(O)₂NR^(o)R^(o), or S(O)₂NR^(o)R^(o), wherein the C₁₋₄ alkyl, C₃₋₁₀ cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-6 membered heteroaryl)-C₁₋₄ alkyl-, (4-7 membered heterocycloalkyl)-C₁₋₄ alkyl-, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₄ haloalkyl are optionally substituted with 1, 2 or 3 R^(q) substituents; R^(g) is selected from hydrogen, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, or (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are optionally substituted with 1, 2, or 3 R^(p) substituents; R^(p) is selected from halo, cyano, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, NHOR^(r), OR^(r), SR^(r), C(O)R^(r), C(O)NR^(r)R^(r), C(O)OR^(r), OC(O)R^(r), OC(O)NR^(r)R^(r), NHR^(r), NR^(r)R^(r), NR^(r)C(O)R^(r), NR^(r)C(O)NR^(r)R^(r), NR^(r)C(O)OR^(r), C(═NR^(r))NR^(r)R^(r), NR^(r)C(═NR^(r))NR^(r)R^(r), NR^(r)C(═NOH)NR^(r)R^(r), NR^(r)C(═NCN)NR^(r)R^(r), S(O)R^(r), S(O)NR^(r)R^(r), S(O)₂R^(r), NR^(r)S(O)₂R^(r), NR^(r)S(O)₂NR^(r)R^(r) or S(O)₂NR^(r)R^(r), wherein the C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are optionally substituted with 1, 2 or 3 R^(q) substituents; R^(e), R^(i), R^(k), R^(o) and R^(r) are independently selected from hydrogen, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5 or 6-membered heteroaryl, 4-6 membered heterocycloalkyl, C₁₋₄ haloalkyl, C₂₋₄ alkenyl, or C₂₋₄ alkynyl, wherein the C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5 or 6-membered heteroaryl, 4-6 membered heterocycloalkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl are optionally substituted with 1, 2 or 3 R^(q) substituents; R^(q) is selected from hydroxy, cyano, amino, halo, COOH, C₁₋₆ haloalkyl, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylthio, C₅₋₆ aryl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, C₃₋₆ cycloalkyl, NHR⁸, NR⁸R⁸, and C₁₋₄ haloalkoxy, wherein the C₁₋₆ alkyl, C₅₋₆ aryl, C₃₋₆ cycloalkyl, 4-6 membered heterocycloalkyl, and 5-6 membered heteroaryl are optionally substituted with halo, hydroxy, cyano, COOH, amino, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₅₋₆ aryl, C₃₋₁₀ cycloalkyl, 5-6 membered heteroaryl and 4-6 membered heterocycloalkyl; R⁸ is C₁₋₆ alkyl.
 7. The compounds of Formula I or its polymorphs, stereoisomers, tautomers, prodrugs, solvates, and pharmaceutically acceptable salts thereof, as claimed in claim 1, is selected from a group consisting of: (S)-1-((7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl) piperidine-2-carboxylic acid (1), N-(2-(((5-methoxy-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl) methyl)amino)ethyl)acetamide (2), (S)-1-((7-((3-(1-(3-(3,3-difluoropyrrolidin-1-yl)propyl)-1H-indol-4-yl)-2-methylbenzyl)oxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylic acid (3), (S)-1-((6-methyl-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylic acid (4), (S)-1-((6-chloro-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylic acid (5), Methyl 7-(((2-acetamidoethyl)amino)methyl)-4-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-indene-5-carboxylate (6), (S)-1-((7-((3′-(3-(3,3-difluoropyrrolidin-1-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-methoxy-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylic acid (7), (S)-1-((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylic acid (8), (S)-1-((5-((5-fluoropyridin-3-yl)methoxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylic acid (9) N-(2-(((5-((5-fluoropyridin-3-yl)methoxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)amino)ethyl)acetamide (10) (S)-5-((5-methoxy-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)-5-azaspiro[2.4]heptane-6-carboxylic acid (11) (S)-1-((7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-5-(2,2,2-trifluoroethoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylic acid (12) N-(2-(((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)amino)ethyl)-N-methylacetamide (13) N-(2-(((5-(1-(3-cyanophenyl)ethoxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)amino)ethyl)acetamide (14) N-(1-((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidin-3-yl)acetamide (15) N-(2-(((7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)amino)ethyl)acetamide (16) 6-((7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)-2-oxa-6-azaspiro[3.3]heptane (17) 2-(hydroxymethyl)-2-(((7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)amino)propane-1,3-diol (18) 1-(((7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)amino)cyclopropane-1-carboxylic acid (19) ((7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)glycine (20) 3-(((7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)amino)propanoic acid (21) N-methyl-N-((7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)glycine (22) 3-(((7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)amino)butanoic acid (23) ((7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)alanine (24) (2S,4R)-4-hydroxy-1-((5-methoxy-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)pyrrolidine-2-carboxylic acid (25) (S)-1-((5-methoxy-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylic acid (26) 1-((4-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-5,6,7,8-tetrahydronaphthalen-1-yl)methyl)piperidine-2-carboxylic acid (27) N-(2-(((6-methyl-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)amino)ethyl)acetamide (28) (2S,4R)-4-hydroxy-1-((6-methyl-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)pyrrolidine-2-carboxylic acid (29) N-(2-(((6-chloro-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)amino)ethyl)acetamide (30) (2S,4R)-1-((6-chloro-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)-4-hydroxypyrrolidine-2-carboxylic acid (31) N-(2-(((7-((3′-(3-(3,3-difluoropyrrolidin-1-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-methoxy-2,3-dihydro-1H-inden-4-yl)methyl)amino)ethyl)acetamide (32) (2S,4R)-1-((7-((3′-(3-(3,3-difluoropyrrolidin-1-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-methoxy-2,3-dihydro-1H-inden-4-yl)methyl)-4-hydroxypyrrolidine-2-carboxylic acid (33) N-(2-(((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)amino)ethyl)acetamide (34) (2S,4R)-1-((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)-4-hydroxypyrrolidine-2-carboxylic acid (35) (S)-1-((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylic acid (36) (S)-1-((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxamide (37) 3-(((4-(((1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)amino)methyl)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)benzonitrile (38) 3-(((4-((2-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)benzonitrile (39) 3-(((4-((3-hydroxypiperidin-1-yl)methyl)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)benzonitrile (40) ((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)glycine (41) (S)-5-((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)-5-azaspiro[2.4]heptane-6-carboxylic acid (42) rac-(1R,6S)-2-((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl) methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)-2-azabicyclo[4.1.0]heptane-1-carboxylic acid (cis, racemic) (43) 4-(((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl) methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)amino)butanoic acid (44) (1R,6S)-2-((5-methoxy-7-((2-methyl-[1,1′-biphenyl]-3-yl) methoxy)-2,3-dihydro-1H-inden-4-yl) methyl)-2-azabicyclo[4.1.0]heptane-1-carboxylic acid (cis, racemic) (45) (S)-1-((5-((5-cyanopyridin-3-yl)methoxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl) methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylic acid (46) (2S,4R)-1-((5-((5-cyanopyridin-3-yl)methoxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)-4-hydroxypyrrolidine-2-carboxylic acid (47) N-(2-(((5-((5-cyanopyridin-3-yl)methoxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)amino)ethyl)acetamide (48) 5-(((4-(((1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)amino)methyl)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)nicotinonitrile (49) (S)-4-((5-((5-cyanopyridin-3-yl)methoxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)morpholine-3-carboxylic acid (50) rac-(1R,6S)-2-((5-((5-cyanopyridin-3-yl)methoxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)-2-azabicyclo[4.1.0]heptane-1-carboxylic acid (cis, racemic) (51) (S)-5-((5-((5-cyanopyridin-3-yl)methoxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)-5-azaspiro[2.4]heptane-6-carboxylic acid (52) N-(2-(((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)(methyl)amino)ethyl)acetamide (53) N-(2-(((5-((4-cyanobenzyl)oxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)amino)ethyl)acetamide (54) (S)-1-((7-((2-cyano-[1,1′-biphenyl]-3-yl)methoxy)-5-methoxy-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylic acid (55) N-(2-(((7-((2-cyano-[1,1′-biphenyl]-3-yl)methoxy)-5-methoxy-2,3-dihydro-1H-inden-4-yl)methyl)amino)ethyl)acetamide (56) (2S,4R)-1-((7-((2-cyano-[1,1′-biphenyl]-3-yl)methoxy)-5-methoxy-2,3-dihydro-1H-inden-4-yl)methyl)-4-hydroxypyrrolidine-2-carboxylic acid (57) 3-(((7-(((1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)amino)methyl)-6-methoxy-2,3-dihydro-1H-inden-4-yl)oxy)methyl)-[1,1′-biphenyl]-2-carbonitrile (58) (S)-4-((7-((2-cyano-[1,1′-biphenyl]-3-yl)methoxy)-5-methoxy-2,3-dihydro-1H-inden-4-yl)methyl)morpholine-3-carboxylic acid (59) ((7-((2-cyano-[1,1′-biphenyl]-3-yl)methoxy)-5-methoxy-2,3-dihydro-1H-inden-4-yl)methyl)glycine (60) (S)-5-((7-((2-cyano-[1,1′-biphenyl]-3-yl)methoxy)-5-methoxy-2,3-dihydro-1H-inden-4-yl)methyl)-5-azaspiro[2.4]heptane-6-carboxylic acid (61) rac-(1R,6S)-2-((7-((2-cyano-[1,1′-biphenyl]-3-yl)methoxy)-5-methoxy-2,3-dihydro-1H-inden-4-yl)methyl)-2-azabicyclo[4.1.0]heptane-1-carboxylic acid (cis, racemic) (62) 2-(1-((7-((2-cyano-[1,1′-biphenyl]-3-yl)methoxy)-5-methoxy-2,3-dihydro-1H-inden-4-yl)methyl)piperidin-2-yl)acetic acid (63) N-(2-(((7-((2-cyano-[1,1′-biphenyl]-3-yl)methoxy)-5-methoxy-2,3-dihydro-1H-inden-4-yl)methyl)(methyl)amino)ethyl)-N-methylacetamide (64) 5-((4-(((2-acetamidoethyl)amino)methyl)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)pentanoic acid (65) 5-((4-(((2-acetamidoethyl)amino)methyl)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)pentanamide (66) (S)-1-((5-(4-carboxybutoxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylic acid (67) (S)-1-((5-((5-amino-5-oxopentyl)oxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylic acid (68) (S)-1-((5-((5-cyanopyridin-3-yl)methoxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl) methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylic acid (69) (2S,4R)-1-((7-((2-cyano-[1,1′-biphenyl]-3-yl)methoxy)-5-((5-cyanopyridin-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)-4-hydroxypyrrolidine-2-carboxylic acid (70) (R)-1-((7-((2-cyano-[1,1′-biphenyl]-3-yl)methoxy)-5-((5-cyanopyridin-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-3-carboxylic acid (71) rac-(1R,6S)-2-((7-((2-cyano-[1,1′-biphenyl]-3-yl)methoxy)-5-((5-cyanopyridin-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)-2-azabicyclo[4.1.0]heptane-1-carboxylic acid (cis racemic) (72) Methyl 4-(((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylate (73) 4-(((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic acid (74) (S)-1-((5-methoxy-7-((2-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylic acid (75) (2S,4R)-4-hydroxy-1-((5-methoxy-7-((2-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)pyrrolidine-2-carboxylic acid (76) (2S)-1-((7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-5-((1-methylpiperidin-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylic acid (77) (S)-1-((5-(4-carboxybutoxy)-7-((2-cyano-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylic acid (78) N-(2-(((5-(4-cyanobutoxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)amino)ethyl)acetamide (79) (S)-1-((5-(4-cyanobutoxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxamide (80) (2S,4R)-1-((5-(4-cyanobutoxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)-4-hydroxypyrrolidine-2-carboxylic acid (81) (S)-1-((5-(((1S,2R)-2-carboxycyclopropyl)methoxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylic acid (82) (1R,2S)-2-(((4-(((2-acetamidoethyl)amino)methyl)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)cyclopropane-1-carboxylic acid (83) (S)-1-((7-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylbenzyl)oxy)-5-methoxy-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylic acid (84) (2S,4R)-1-((7-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylbenzyl)oxy)-5-methoxy-2,3-dihydro-1H-inden-4-yl)methyl)-4-hydroxypyrrolidine-2-carboxylic acid (85) N-(2-(((5-((3-cyanobenzyl)oxy)-7-((2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)amino)ethyl)acetamide (86) N-(2-(((5-((3-cyanobenzyl)oxy)-7-((4′-fluoro-2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)amino)ethyl)acetamide (87) (S)-1-((5-((3-carbamoylbenzyl)oxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylic acid (88) 3-(((4-(aminomethyl)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)benzonitrile (89) N-((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl) methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)acetamide (90) 6-acetamido-N-((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)hexanamide (91) 3-(((4-((dimethylamino)methyl)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)benzonitrile (92) 5-(((4-(((2-acetamidoethyl)amino)methyl)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)nicotinic acid (93) 5-(((4-(((2-acetamidoethyl)amino)methyl)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)nicotinamide (94) 3-(((4-(((2-acetamidoethyl)amino)methyl)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)benzamide (95) (S)-1-((3-methoxy-1-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)methyl)piperidine-2-carboxylic acid (96) N-(2-(((3-methoxy-1-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)methyl)amino)ethyl)acetamide (97) (S)-4-((5-methoxy-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)morpholine-3-carboxylic acid (98) 5-((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid (99)
 8. A process of preparation of compounds of Formula I, as claimed in claim 1 or its polymorphs, stereoisomers, tautomers, prodrugs, solvates, and pharmaceutically acceptable salts thereof.
 9. The process of preparation of compounds of Formula I as claimed in claim 8, comprising: (a) reacting compounds of Formula I (a) with substituted aliphatic, aromatic, heterocyclic and cyclic amines to obtain compounds of Formula I

wherein the X₁ of Formula I (a) and Formula I is selected from —CH₂O—, —OCH₂—, —C(O)NH— or —NHC(O)—; R₄ of Formula I (a) and Formula I is selected from hydrogen, C₁₋₆ alkyl, —C(O)OR_(a1), C(O)NR_(b1)R_(c1), C₅₋₆ aryl, or C₁₋₆ heteroaryl, wherein C₁₋₆ alkyl is optionally substituted with one or more of the groups selected from the group consisting of hydrogen, hydroxyl, amino, —C(O)OR_(a1), C(O)NR_(b1)R_(c1), C₅₋₆ aryl, and C₁₋₆ heteroaryl; R_(a1), R_(b1), and R_(c1) are independently selected from hydrogen or C₁₋₆ alkyl; X of Formula I (a) and Formula I is selected from CR₃ or N; R₁, R₂, R₆, and R₇ of Formula I (a) and Formula I are independently selected from hydrogen, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-14 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a), SR^(a), NHOR^(a), C(O)R^(a), C(O)NR^(a)R^(a), C(O)OR^(a), OC(O)R^(a), OC(O)NR^(a)R^(a), NHR^(a), NR^(a)R^(a), NR^(a)C(O)R^(a), NR^(a)C(O)OR^(a), NR^(a)C(O)NR^(a)R^(a), C(═NR^(a))R^(a), C(═NR^(a))NR^(a)R^(a), NR^(a)C(═NR^(a))NR^(a)R^(a), NR^(a)S(O)R^(a), NR^(a)S(O)₂R^(a), NR^(a)S(O)₂NR^(a)R^(a), S(O)R^(a), S(O)NR^(a)R^(a), S(O)₂R^(a), or S(O)₂NR^(a)R^(a), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆_10 aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-14 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, are independently optionally substituted with 1, 2, 3, or 4 R^(b) substituents; R^(a) is selected from hydrogen, cyano, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, or (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are independently optionally substituted with 1, 2, 3, 4, or 5 R^(d) substituents; R^(b) is selected from halo, hydroxy, cyano, amino, nitro, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, NHOR^(c), OR^(c), SR^(c), C(O)R^(c), C(O)NR^(c)R^(c), C(O)OR^(c), OC(O)R^(c), OC(O)NR^(c)R^(c), C(═NR^(c))NR^(c)R^(c), NR^(c)C(═NR^(c))NR^(c)R^(c), NHR^(c), NR^(c)R^(c), NR^(c)(O)R^(c), NR^(c)(O)OR^(c), NR^(c)C(O)NR^(c)R^(c), NR^(c)S(O)R^(c), NR^(c)S(O)₂R^(c), NR^(c)S(O)₂NR^(c)R^(c), S(O)R^(c), S(O)NR^(c)R^(c), S(O)₂R^(c) or S(O)₂NR^(c)R^(c); wherein the C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆_10 aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are optionally substituted with 1, 2, or 3 R^(d) substituents; R^(c) is selected from hydrogen, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, or (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are optionally substituted with 1, 2, 3, 4, or 5 R^(f) substituent; R^(d) is selected from cyano, amino, C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, NHOR^(e), OR^(e), SR^(e), C(O)R^(e), C(O)NR^(e)R^(e), C(O)OR^(e), OC(O)R^(e), OC(O)NR^(e)R^(e), NHR^(e), NR^(e)R^(e), NR^(e)C(O)R^(e), NR^(e)C(O)NR^(e)R^(e), NR^(e)C(O)OR^(e), C(═NR^(e))NR^(e)R^(e), NR^(e)C(═NR^(e))NR^(e)R^(e), NR^(e)C(═NOH)NR^(e)R^(e), NR^(e)C(═NCN)NR^(e)R^(e), S(O)R^(e), S(O)NR^(e)R^(e), S(O)₂R^(e), NR^(e)S(O)₂R^(e), NR^(e)S(O)₂NR^(e)R^(e), or S(O)₂NR^(e)R^(e), wherein the C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are optionally substituted with 1, 2, or 3 R^(f) substituents; R^(f) is selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, halogen, CN, NHOR^(g), R^(g), SR^(g), C(O)R^(g), C(O)NR^(g)R^(g), C(O)OR^(g), OC(O)R^(g), OC(O)NR^(g)R^(g), NHR^(g), NR^(g)R^(g), NR^(g)C(O)R^(g), NR^(g)C(O)NR^(g)R^(g), NR^(g)C(O)OR^(g), C(═NR^(g))NR^(g)R^(g), NR^(g)C(═NR^(g))NR^(g)R^(g), S(O)R^(g), S(O)NR^(g)R^(g), S(O)₂R^(g), NR^(g)S(O)₂R^(g), NR^(g)S(O)₂NR^(g)R^(g), or S(O)₂NR^(g)R^(g); wherein the C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are optionally substituted with 1, 2, 3, 4, or 5 R^(n) substituents; R^(g) is selected from hydrogen, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, or (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are optionally substituted with 1, 2, or 3 R^(p) substituents; R^(n) is selected from cyano, halo, C₁₋₄ alkyl, C₃₋₁₀ cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-6 membered heteroaryl)-C₁₋₄ alkyl-, (4-7 membered heterocycloalkyl)-C₁₋₄ alkyl-, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl, R^(o), NHOR^(o), OR^(o), SR^(o), C(O)R^(o), C(O)NR^(o)R^(o), C(O)OR^(o), OC(O)R^(o), OC(O)NR^(o)R^(o), NHR^(o), NR^(o)R^(o), NR^(o)C(O)R^(o), NR^(o)C(O)NR^(o)R^(o), NR^(o)C(O)OR^(o), C(═NR)NR^(o)R^(o), NR^(o)C(═NR^(o))NR^(o)R^(o), S(O)R^(o), S(O)NR^(o)R^(o), S(O)₂R^(o), NR^(o)S(O)₂R^(o), NR^(o)S(O)₂NR^(o)R^(o), or S(O)₂NR^(o)R^(o), wherein the C₁₋₄ alkyl, C₃₋₁₀ cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-6 membered heteroaryl)-C₁₋₄ alkyl-, (4-7 membered heterocycloalkyl)-C₁₋₄ alkyl-, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₄ haloalkyl are optionally substituted with 1, 2 or 3 R^(q) substituents; R^(p) is selected from halo, cyano, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, NHOR^(r), OR^(r), SR^(r), C(O)R^(r), C(O)NR^(r)R^(r), C(O)OR^(r), OC(O)R^(r), OC(O)NR^(r)R^(r), NHR^(r), NR^(r)R^(r), NR^(r)C(O)R^(r), NR^(r)C(O)NR^(r)R^(r), NR^(r)C(O)OR^(r), C(═NR^(r))NR^(r)R^(r), NR^(r)C(═NR^(r))NR^(r)R^(r), NR^(r)C(═NOH)NR^(r)R^(r), NR^(r)C(═NCN)NR^(r)R^(r), S(O)R^(r), S(O)NR^(r)R^(r), S(O)₂R^(r), NR^(r)S(O)₂R^(r), NR^(r)S(O)₂NR^(r)R^(r) or S(O)₂NR^(r)R^(r), wherein the C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are optionally substituted with 1, 2 or 3 R^(q) substituents; R^(e), R^(i), R^(k), R^(o) and R^(r) are independently selected from hydrogen, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5 or 6-membered heteroaryl, 4-6 membered heterocycloalkyl, C₁₋₄ haloalkyl, C₂₋₄ alkenyl, or C₂₋₄ alkynyl, wherein the C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5 or 6-membered heteroaryl, 4-6 membered heterocycloalkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl are optionally substituted with 1, 2 or 3 R^(q) substituents; R^(q) is selected from hydroxy, cyano, amino, halo, COOH, C₁₋₆ haloalkyl, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylthio, C₅₋₆ aryl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, C₃₋₆ cycloalkyl, NHR⁸, NR⁸R⁸, and C₁₋₄ haloalkoxy, wherein the C₁₋₆ alkyl, C₅₋₆ aryl, C₃₋₆ cycloalkyl, 4-6 membered heterocycloalkyl, and 5-6 membered heteroaryl are optionally substituted with halo, hydroxy, cyano, COOH, amino, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₅₋₆ aryl, C₃₋₁₀ cycloalkyl, 5-6 membered heteroaryl and 4-6 membered heterocycloalkyl; R⁸ is C₁₋₆ alkyl; m is 1 or 2; Ring A is selected from substituted or unsubstituted C₅₋₁₀ aryl, substituted or unsubstituted C₃₋₆ cycloalkyl, and substituted or unsubstituted 6-10 membered monocyclic saturated or unsaturated heterocyclic ring with 1-3 heteroatoms selected from N, S or O; Ring B is selected from C₅₋₁₀ aryl, C₃₋₆ cycloalkyl, 5-10 membered monocyclic saturated or unsaturated heterocyclic ring with 1-3 heteroatoms selected from N, S or O, with substituted amines in the presence of solvents to obtain compounds of Formula I.
 10. A pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof as claimed in claim 1, together with a pharmaceutically acceptable carrier, optionally in combination with one or more other pharmaceutical compositions.
 11. The pharmaceutical composition as claimed in claim 10, wherein the composition is in the form selected from the group consisting of a tablet, capsule, powder, syrup, solution, aerosol and suspension.
 12. A method for the treatment and/or prevention of various diseases, including cancer and infectious diseases, comprising administering to a subject suffering from the proliferative disorder or cancer a therapeutically effective amount of the compound of Formula I as claimed in claim 1, with other clinically relevant cytotoxic agents or non-cytotoxic agents or with other clinically relevant immune modulators agents to a subject in need thereof.
 13. (canceled)
 14. (canceled)
 15. (canceled)
 16. A method for the treatment and/or prevention of various diseases, including cancer and infectious diseases, comprising administering to a subject suffering from the proliferative disorder or cancer the pharmaceutical composition as claimed in claim 10, with other clinically relevant cytotoxic agents or non-cytotoxic agents or with other clinically relevant immune modulators agents to a subject in need thereof. 